2013 Archived Content

Engineering Stream

15th Annual
Phage and Yeast Display of Antibodies and Recombinant Proteins

April 29-30, 2013

Phage and yeast display are essential tools for engineering the next generation of antibody libraries.  The technology is being exploited for half life extension, epitope mapping, membrane targets, blood-brain-barrier entry, and intracellular targets.  Ligands for previously intractable targets are being derived through directed evolution for a spectrum of novel constructs, including bispecific antibodies and ADCs, antibody fragments and alternative scaffolds.  Deep sequencing of antibody libraries is improving library diversity and yielding drug candidates with improved efficacy.  Plan to attend this year's meeting to see how to improve the capacity for drug candidates to be developed, manufactured and scaled-up.

Scientific Advisory Board

Andrew M. Bradbury, M.B. B.S., Ph.D., Staff Scientist, Biosciences, Los Alamos National Laboratory
David Lowe, Ph.D., Fellow, R&D, Department of Antibody Discovery and Protein Engineering,
Aaron K. Sato, Ph.D., Vice President of Research, Sutro Biopharma
Gregory A. Weiss, Ph.D., Professor, Departments of Chemistry, Molecular Biology & Biochemistry, University of California, Irvine
K. Dane Wittrup, Ph.D., J.R. Mares Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology


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7:00 am Conference Registration and Morning Coffee

8:30 Chairperson's Opening Remarks

Gregory A. Weiss, Ph.D., Professor, Chemistry, Molecular Biology & Biochemistry, UC Irvine


8:40 Challenging Targets for Phage Display

James A. WellsJames A. Wells, Ph.D., Professor and Chair, Pharmaceutical Chemistry, UCSF

9:25 Ubiquitin Variants as Potent Inhibitors and Activators of Enzymes in the Ubiquitin Pathway

Sachdev SidhuSachdev Sidhu, Ph.D., Associate Professor, Banting and Best Department of Medical Research, University of Toronto

Ubiquitin variants have been developed as inhibitors and activators of deubiquitinases and ubiquitin ligases. Structural studies reveal the molecular details for enhanced affinity and selectivity. The ubiquitin variants can be expressed intracellularly to modulate enzyme function in live cells.

10:10 Grand Opening Coffee Break in Exhibit Hall with Poster Viewing

Improving Developability of Proteins 

11:05 Chairperson's Remarks

K. Dane Wittrup, Ph.D., J.R. Mares Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology

11:10 Towards High-Affinity, Aggregation-Resistant Domain Antibodies by Design

Peter TessierPeter Tessier, Ph.D., Assistant Professor, Chemical & Biological  Engineering, Ctr for Biotechnology & Interdisciplinary Studies, Rensselaer Polytechnic Institute

We have developed a method for designing the complementarity-determining regions (CDRs) of domain antibodies to recognize misfolded (aggregated) proteins linked to Alzheimer's and Parkinson's disease with nanomolar binding affinity. Here we will discuss our findings of how such domain antibodies can be engineered to possess both high affinity and solubility despite that they display hydrophobic CDRs to mediate conformation- and sequence-specific binding.

11:40 Engineering Drug-Like Properties of Therapeutic Proteins

Andrew BuchananAndrew Buchanan, Ph.D., Sr Scientist, Protein Engineering, MedImmune Ltd.

Proteins have evolved in nature to fulfill a defined in vivo function but may not meet critical quality requirements for clinical development as therapeutics. Case studies will be presented on improving stability and expression of therapeutic proteins using directed evolution and rational design strategies.

12:10 pm Automated High-Throughput Antibody Discovery and Optimization

Christopher Smith, Ph.D., Scientific Consultant, Biologics, Genedata Inc. 

Together with leading biopharmaceutical companies, we have developed Genedata Biologics, a workflow system that streamlines laborious, manual laboratory processes in antibody screening, protein engineering and production. We present concrete screening automation use cases from working with phage, yeast, mRNA display, and hybridomas and B-cells. We also present our novel high-throughput in silico cloning tools for systematic generation of next-generation antibody molecules, including bispecifics, and their subsequent automated expression, purification, and characterization.  

Morphosys12:40 Luncheon Presentation I: When Worlds Collide: Antibody Technologies and GPCRs  

Stefanie Urlinger, Ph.D., Director, Discovery Alliances & Technologies, MorphoSys AG 

After decades of antibody discovery, two major challenges remain largely unmet: The reliable generation of antibody drug candidates with favorable biophysical properties and the targeting of so far inaccessible antigens, most importantly GPCRs.Data on our antibody library Ylanthia, which consistently produces fully human antibodies with favorable developability profile and on targeting of GPCRs by phage display will be presented.

1:10 Luncheon Presentation II (Sponsorship Opportunity Available) or Lunch on Your Own 

Improving Developability of Proteins (Cont.) 

2:00 Chairperson's Remarks

K. Dane Wittrup, Ph.D., J.R. Mares Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology;  Co-Founder, Adimab

2:05 Developability by Design

K. Dane WittrupK. Dane Wittrup, Ph.D., J.R. Mares Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology;  Co-Founder, Adimab

Efficient mammalian expression, high solubility, and low nonspecific stickiness ("developability") can be the exception for antibodies isolated from artificial repertoires displayed as fragments on phage, necessitating considerable post-selection screening, lead optimization, and formulation effort. A more-human preimmune repertoire, eucaryotic selection host, and high-throughput anti-stickiness counterselection results in routine isolation of highly developable lead antibodies.

2:35 Stability Engineering of the Human Antibody Repertoire Using Phage Display and X-Ray Crystallography

Daniel ChristDaniel Christ, Ph.D., Group Leader, Immunology Department; Director, Therapeutic Antibody Development, Garvan Institute of Medical Research

Here we outline general phage display and structural strategies that allow the stability engineering of common human VH and VL families. Our work opens up routes towards antibody therapeutics that are not only fully human, but also stable and aggregation resistant.

3:05 Discovery, Characterization, and Manufacturing of Next Generation ADC's and Bispecific Antibodies by Cell Free Protein Synthesis

Christopher ThanosChristopher Thanos, Ph.D., Director, Protein Engineering, Sutro Biopharma, Inc.

Sutro has developed significant improvements in a biologics discovery pipeline for the production of next generation protein therapeutics. Using our OCFS based antibody selection technology, we have produced large, diverse libraries that significantly surpass typical limits. Selected fragments are reformatted into IgG's or bispecific antibodies prior to rapid, quantitative, HTS screening in OCFS at high titers.

3:35 Best Poster Presentation: Rapid, Multiplexed Microfluidic Phage Display

Kellye Cung, Princeton University

3:50 Best Poster Presentation: Dissecting Cell Signaling Network Rewiring with Phage Display Generated Synthetic Antibodies

Frederic A. Fellouse, Ph.D., Postdoctoral Fellow, Samuel Lunenfeld Research Institute, University of Toronto

4:05 Refreshment Break in the Exhibit Hall with Poster Viewing

4:45 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.

TABLE: Using Microfluidics in Phage Display

Moderator: Michael C. McAlpine, Ph.D., Assistant Professor, Chemical and Biological Engineering, Princeton University

   • Should the entire phage display process be done in microfluidics or just some portions of it? 
   • What are the advantages of microfluidic phage display approaches vs multi-well plates?
   • Could microfluidics supply additional, novel functionalities and features to conventional phage display?
   • Can microfluidics reduce time and cost of phage display while improving stringency?
   • Will the targets/applications of phage display in microfluidic systems be the same as those in conventional phage display?

TABLE: Synthetic Antibody Technologies to Produce Therapeutic Agents

Moderator: Jonathan R. Lai, Ph.D., Assistant Professor, Biochemistry, Albert Einstein College of Medicine

   • Library considerations: Which libraries work best? To what extent does library size matter?
   • Target selection: Which targets are most worthwhile pursuing?
   • Screening: Which format is best? What is the success rate? How can we bias for bi-specifics?
   • Validation: What are the best indicators for in vivo efficacy?
   • PK/PD: How similar are synthetic antibodies to naturally-derived antibodies?

TABLE: Deep Sequencing of Phage and Yeast Libraries

Moderator: Ratmir Derda, Ph.D., Principal Investigator, Alberta Glycomics Centre; Assistant Professor, Department of Chemistry, University of Alberta, Edmonton

   • Sequencing machines. Personal preferences, availabilities, quality, turnaround
   • What are the prices per run (different machines, different places) around North America? What is the economic future of deep sequencing? More for same price? Same number for less?
   • Sample prep: papers in journals vs. brochures. Phage library preparation vs standard genome prep.
   • Quality, quality, quality. What to do with mutations, truncations, and other errors "invisible" to Phred score.
   • Can deep sequencing avoid the "analysis crisis" of DNA microarrays in late 90's (everyone collects data, nobody analyses it properly).
   • Statistics in deep sequencing? Back to school? Text books? courses?

TABLE: Directed Evolution of DNA Polymerases

Moderator: Floyd E. Romesberg, Ph.D., Associate Professor, Chemistry, The Scripps Research Institute

   • Unnatural/modified DNA and the challenges of replication
   • Starting points – the natural polymerases
   • Generation of diversity
   • Selection strategies
   • Selection pressure

5:45 - 6:45 Welcoming Reception in Exhibit Hall with Poster Viewing

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