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8:00 am Registration and Morning Coffee
8:25 Chairperson’s Opening Remarks
K. Dane Wittrup, Ph.D., J.R. Mares Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
8:30 de novo Selection of High Affinity Antibodies from Synthetic Antibody Libraries Displayed on Phage as pIX-Fusion Proteins
John Wheeler, Ph.D., Senior Research Scientist, Biologics Research, Centocor
We report here the first combinatorial synthetic Fab libraries displayed on pIX, constructed on twelve scaffolds representing frequently used genes in human antibodies. After selection on a diverse panel of proteins, numerous specific, nanomolar-affinity Fabs were isolated. Applying an integrated affinity maturation process, selected antibodies yielded low picomolar affinities.
9:00 Next-Generation Sequencing Technologies Applied to Antibody Display: By-Passing Primary Screening
Nicolas Fischer, Ph.D., Head of Protein Engineering, NovImmune SA
In recent years novel technologies have allowed unprecedented DNA sequencing capacity that has revolutionized whole genome sequencing. We have applied the Illumina sequencing platform to different steps of phage display selection of antibody fragments. We used a specially designed scFv library in order to follow the evolution of virtually all antibody sequences during the selection process. This approach also allows for the direct identification of potential hits without upfront activity screening.
9:30 Engineered Bispecific Proteins that Target Multiple Tumor Vasculature Receptors
Jennifer Cochran, Ph.D., Assistant Professor, Bioengineering, Stanford Medical Center
There is significant crosstalk between the cell signaling pathways of receptors expressed on the tumor vasculature; therefore, bispecific agents that target multiple receptors offer promise for improved inhibition of tumor angiogenesis and metastasis. We used a natural growth factor ligand as a scaffold to engineer bispecific proteins that bind to both VEGFR and alphavbeta3 integrin with low nanomolar affinities. These engineered proteins strongly inhibit ligand-mediated receptor phosphorylation and cell proliferation compared with protein variants that bind only one receptor, and are currently being evaluated in murine tumor models.
10:00 Coffee Break, Poster and Exhibit Viewing
10:45 A “Super-Library” of Alternate Scaffolds for Engineering Molecular Recognition
Balaji Rao, Ph.D., Assistant Professor, Chemical Engineering, North Carolina State University
A “super-library” of alternate scaffolds for engineering molecular recognition. We have created a “super-library” of alternate scaffold proteins where multiple different topologies have been randomized. Here we present our results comparing this super-library with a single-scaffold library having much higher sequence diversity. A comparison of yeast surface display and mRNA display methods for library screening, in the context of this problem, is also presented.
11:15 Phage-Encoded Bicyclic Peptides
Christian Heinis, Ph.D., Professor, Laboratory of Therapeutic Peptides and Proteins, Ecole Polytechnique Fédéral de Lausanne (EPFL)
With Sir Greg Winter, I had developed at the Laboratory of Molecular Biology (LMB) in Cambridge, UK, combinatorial libraries of phage-encoded bicyclic peptides by chemically cyclizing linear peptides on phage. From these libraries, we were able to isolate peptide macrocycle structures with high affinity and specificity for disease related serine proteases.
11:45 Generation of Nanobodies® With fM Affinities: Exploration of Different Methods for Affinity Maturation
Joost Kolkman, Ph.D., Associate Director, Discovery, Ablynx
12:15 pm Luncheon Presentations (Sponsorship Opportunities Available) or Lunch on Your Own
2:00 Chairperson’s Remarks
David Lowe, Ph.D., Head, Display Technology, RI & A, MedImmune, Inc.
2:05 Thermodynamic and Information-Based Design of IgG-Like Bispecific Antibodies
Stephen J. Demarest, Ph.D., Senior Scientist, Protein Chemistry, Biogen IDEC, Inc.
We use thermal unfolding experiments to define stability constraints within antibody and scFv molecules. We have devised sequence-based methodologies to generate highly stable antibody domains for the construction of robust IgG-like bispecific antibodies. Some successful protein engineering applications will be described.
2:35 Aggregation-Resistant Human Antibody Domains through Directed Evolution
Daniel Christ, Ph.D., Senior Lecturer, Garvan Institute of Medical Research and Senior Lecturer (conj.), Faculty of Medicine, The University of New South Wales
Human antibody variable domains tend to aggregate in isolation. In addition, the aggregation-propensities of larger antibody therapeutics are often influenced by their variable domains. We have recently demonstrated that human variable domains can be engineered to resist aggregation. The engineered domains withstand challenging conditions, such as high temperature and acidic pH. Progress on the development of repertoires of such domains will be discussed. Aggregation-resistant single domains are a promising class of antibody fragments and provide robust building blocks for the generation of larger antibody therapeutics.
3:05 Antibody Selection from Immunoglobulin Gene Libraries Expressed in Mammalian CellsSponsored by
Ernest S.Smith , Senior Vice President, Research, CSO, Vaccinex, Inc.
Utilizing a vaccinia virus based library technology we have developed an antibody discovery technology that enables efficient selection of full length IgG antibodies from highly diverse immunoglobulin gene libraries expressed in mammalian cells. This technology can be used either for de novo antibody selection or for the robust conversion of a non-human antibody into a panel of fully human antibodies with similar or even improved affinity and functional activity. This technology has a number of advantages, including a built in selection for full length IgG antibodies that are efficiently expressed in mammalian cells.
3:35 Refreshment Break, Poster and Exhibit Viewing
4:15 Designing Quality in Antibodies: In Silico Aggregation Screening and Protein Engineering Methodologies to Improve Developability and Safety Profiles
Jesús Zurdo, Ph.D., Head, Advanced Protein Technologies, Lonza Biologics plc
Protein aggregation and low stability imposes severe restraints in the development of biopharmaceuticals, potentially increasing the risks of undesired immune responses in patients. Predictive algorithms can be used during lead selection to screen out polypeptides with aggregation / stability issues early on in the development process. Such methodologies have also been successfully applied to re-designing therapeutic antibodies with improved stability properties.
4:45 Human Antibody Discovery and Optimization in Yeast
Michael J. Feldhaus, Ph.D., Senior Director, Antibody Engineering, Adimab, Inc.
We have developed an integrated platform for the discovery and optimization of human IgGs in yeast. Unprecedented speed from antigen to panels of human IgG protein is attained. Selection of binders within the IgG format results in desirable bioprocess phenotypes for the selected antibodies.
5:15 End of Conference
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