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目錄下載(PDF)
產業會議彙總曆
CSS
作為探查構造之有作用的抗體
12:00
Registration Opens
1:30
Announcements
1:35
Co-Chairperson's Opening Remarks
Jamie K. Scott, M.D., Ph.D., Professor, Dept. Molecular Biology, Biochemistry and Faculty of Health Sciences, Simon Fraser University, Canada
Sachdev Sidhu, Ph.D., Professor, Department of Molecular Genetics, University of Toronto, Canada
Jamie K. Scott, M.D., Ph.D., Professor, Dept. Molecular Biology, Biochemistry and Faculty of Health Sciences, Simon Fraser University, Canada
Sachdev Sidhu, Ph.D., Professor, Department of Molecular Genetics, University of Toronto, Canada
1:45
Synthetic Antibodies: Structure and Function
Phage displayed synthetic antibody libraries built on a single framework have simplified and expedited the discovery of highly stable antibodies for protein structural studies. Despite the simplicity of library design, synthetic antibodies have proven to be at least as versatile for generating high affinity antibodies against diverse protein antigens. Moreover, synthetic antibodies exhibit superior performance in crystallization studies due to their stable nature and predictable behavior.
Sachdev Sidhu, Ph.D., Professor, Department of Molecular Genetics, University of Toronto, Canada
Phage displayed synthetic antibody libraries built on a single framework have simplified and expedited the discovery of highly stable antibodies for protein structural studies. Despite the simplicity of library design, synthetic antibodies have proven to be at least as versatile for generating high affinity antibodies against diverse protein antigens. Moreover, synthetic antibodies exhibit superior performance in crystallization studies due to their stable nature and predictable behavior.
Sachdev Sidhu, Ph.D., Professor, Department of Molecular Genetics, University of Toronto, Canada
2:15
The Chaperone-Enabled Biology-Structure (CEBS) Technology Platform
The CEBS technology generates and utilizes customized "Synthetic Affinity Binders" (sABs) as crystallization chaperones for recalcitrant protein systems. Highly controlled phage display selection strategies allow for targeting sABs that can: bind to a predetermined region on a protein's surface, trap a desired conformational state and capture and stabilize a transient protein-protein complex. By studying both structure and function using the same identical set of sABs, we can determine the functional importance of a specific region/conformation/complex that will provide a direct link between structure and function.
Anthony Kossiakoff, Ph.D., Otho S. A. Sprague Professor and Chair, Department of Biochemistry and Molecular Biology, University of Chicago
The CEBS technology generates and utilizes customized "Synthetic Affinity Binders" (sABs) as crystallization chaperones for recalcitrant protein systems. Highly controlled phage display selection strategies allow for targeting sABs that can: bind to a predetermined region on a protein's surface, trap a desired conformational state and capture and stabilize a transient protein-protein complex. By studying both structure and function using the same identical set of sABs, we can determine the functional importance of a specific region/conformation/complex that will provide a direct link between structure and function.
Anthony Kossiakoff, Ph.D., Otho S. A. Sprague Professor and Chair, Department of Biochemistry and Molecular Biology, University of Chicago
2:45
Application of Antibodies in Structural Genomics
Structural Genomics (high throughput structural biology) initiatives have generated large repertoires of recombinant proteins that make excellent antigens for the generation of recombinant antibodies and related affinity reagents. We are generating large numbers of such reagents to human proteins involved in epigenetic and ubiquitin signaling pathways. I will discuss the application of these reagents for understanding protein structure, function and their cellular biology.
Cheryl Arrowsmith, Ph.D., Chief Scientist, SGC-Toronto, Senior Scientist, Ontario Cancer Institute, Professor, Medical Biophysics, University of Toronto, Canada
Structural Genomics (high throughput structural biology) initiatives have generated large repertoires of recombinant proteins that make excellent antigens for the generation of recombinant antibodies and related affinity reagents. We are generating large numbers of such reagents to human proteins involved in epigenetic and ubiquitin signaling pathways. I will discuss the application of these reagents for understanding protein structure, function and their cellular biology.
Cheryl Arrowsmith, Ph.D., Chief Scientist, SGC-Toronto, Senior Scientist, Ontario Cancer Institute, Professor, Medical Biophysics, University of Toronto, Canada
3:15
Networking Refreshment Break
3:45
Structure-Based Engineering of Anti-Peptide Antibodies
Currently, detection of biologically relevant peptides and defined peptide epitopes (e.g. phoshopeptides) relies upon the generation of monoclonal antibodies through hybridoma technology, which is costly and low throughput. Our work aims to apply a mixture of structure-based and combinatorial methods to construct both large (>1010), diverse antibody libraries as well as small, focused libraries that efficiently target peptide epitopes. We will discuss the ongoing development of antibodies targeted to specific peptides involved in apoptotic signaling.
James T. Koerber, Ph.D., Life Sciences Research Fellow, University of California, San Francisco
Currently, detection of biologically relevant peptides and defined peptide epitopes (e.g. phoshopeptides) relies upon the generation of monoclonal antibodies through hybridoma technology, which is costly and low throughput. Our work aims to apply a mixture of structure-based and combinatorial methods to construct both large (>1010), diverse antibody libraries as well as small, focused libraries that efficiently target peptide epitopes. We will discuss the ongoing development of antibodies targeted to specific peptides involved in apoptotic signaling.
James T. Koerber, Ph.D., Life Sciences Research Fellow, University of California, San Francisco
4:15
Dual Action Hot Spot: How does Monospecific Antibody Evolve Dual Binding Specificity?
We have demonstrated that a monospecific antibody may recruit a secondary specificity through mutation at the antigen binding site and evolve high affinity dual specificity toward two very different antigens. I will discuss the structure/function studies of two such two-in-one antibodies against HER2/VEGF and EGFR/HER3, and the molecular basis of the evolution of the second binding specificity while retaining its first binding specificity.
Germaine Fuh, Ph.D., Senior Scientist, Antibody Engineering, Genentech Inc.
We have demonstrated that a monospecific antibody may recruit a secondary specificity through mutation at the antigen binding site and evolve high affinity dual specificity toward two very different antigens. I will discuss the structure/function studies of two such two-in-one antibodies against HER2/VEGF and EGFR/HER3, and the molecular basis of the evolution of the second binding specificity while retaining its first binding specificity.
Germaine Fuh, Ph.D., Senior Scientist, Antibody Engineering, Genentech Inc.
4:45
Antibodies Against the Ebola Virus
Understanding the components of an effective immune response against the ebolaviruses is a major goal of biodefense. We will present X-ray structures of four unique mAbs against ebolaviruses in complex with their glycoprotein epitopes. Two, human kZ52 and murine 16F6, bind the base of the trimeric envelope glycoprotein and appear to function by blocking conformational changes required for membrane fusion. Two others, 14G7 and 13F6, recognize the unusual, heavily glycosylated mucin-like domains of the viral glycoprotein.
Erica Ollmann Saphire, Ph.D., Associate Professor, Immunology and Microbial Science, The Scripps Research Institute
Understanding the components of an effective immune response against the ebolaviruses is a major goal of biodefense. We will present X-ray structures of four unique mAbs against ebolaviruses in complex with their glycoprotein epitopes. Two, human kZ52 and murine 16F6, bind the base of the trimeric envelope glycoprotein and appear to function by blocking conformational changes required for membrane fusion. Two others, 14G7 and 13F6, recognize the unusual, heavily glycosylated mucin-like domains of the viral glycoprotein.
Erica Ollmann Saphire, Ph.D., Associate Professor, Immunology and Microbial Science, The Scripps Research Institute
5:15
Workshop Ends
Workshop: Sunday | Main Conference: Monday | Tuesday | Wednesday | Thursday
7:15
Registration, Networking Coffee
7:45
Announcements
Session I: 抗體的構造與力學及膜受容體標的
8:00
Chairperson's Opening Remarks and Keynote Introduction
Andreas Plückthun, Ph.D., Professor of Biochemistry, Department of Biochemistry, University of Zürich, Switzerland
Andreas Plückthun, Ph.D., Professor of Biochemistry, Department of Biochemistry, University of Zürich, Switzerland
Keynote Presentions
8:15
Broad Antibody Neutralization of Influenza Virus and HIV-1Influenza and HIV-1 continue to constitute significant threats to global health. We have determined structures of several potent, broadly neutralizing antibodies against a variety of different and novel epitopes on the HIV-1 and flu surface glycoproteins that include the highly conserved stem fusion region, receptor binding site and the glycans themselves. The structural and functional information can be used to aid in structure-assisted vaccine designs for HIV-1 and for a universal flu vaccine.
Ian Wilson, D.Phil., Hansen Professor of Structural Biology, The Scripps Research Institute
9:00
Structures of GPCRs Interacting with Ligands, Drugs, and Antibody Fragments in Phospholipid BilayersGPCRs remain a largely untapped resource as pharmaceutical targets. There are estimates that approximately equal numbers of GPCRs are susceptible to intervention by small molecules and antibody fragments. The role of structural biology in drug screening and optimization is well established. Therefore, our first priority has been to develop a general NMR method for determining the structures of membrane proteins, like GPCRs, in their native bilayer environment. This will enable the local and conformation effects of drugs and antibody fragments to be described at atomic resolution, accelerating the process of developing therapeutics.
Stanley J. Opella, Ph.D., Professor, Chemistry and Biochemistry, University of California, San Diego
9:45
Networking Refreshment Break
10:15
Structure/Function of HGF/SF and MET as a Basis for Therapeutic TargetingThe polypeptide growth factor HGF/SF and its receptor MET, the product of the proto-oncogene c-MET, have essential roles in embryogenesis and tissue regeneration but also play a major way in human cancer and, specifically, in the early stages of metastasis. This talk will discuss the available data on he structure of HGF/SF and MET as a basis for the development of small molecule inhibitors of the MET kinase and anti-HGF/SF and anti-MET antibodies for cancer therapy.
Ermanno Gherardi, M.D., Ph.D., Scientist, Medical Research Council Laboratory of Molecular Biology, United Kingdom
11:00
A New Mechanism for Allosteric Regulation of EGFR Family MembersThe epidermal growth factor receptor (EGFR) is generally viewed as a "prototypic" receptor tyrosine kinase (RTK), and it is the target of several important cancer therapeutics. However, as mechanistic studies advance it becomes increasingly clear that EGFR and other ErbB family members have unique properties that are not shared by other RTKs. Outlining our structural and biochemical studies, I will describe a new mechanism for allosteric regulation of EGFR focusing on the extracellular and juxtamembrane regions - which has significant implications for function and therapeutic targeting.
Mark A. Lemmon, Ph.D., Professor and Chair, Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania
11:45
Lunch on Your Own
Technology Workshop
1:15
We describe a platform for generating and optimizing hMABs under mammalian folding conditions by dsDNA display of fully human libraries. Sequencing of thousands of hits provides an early read on the function, affinity and specificity of lead candidates. We have affinity matured these VH domains using a rapid framework optimization that maintains their fully human character. A novel VL pairing method has been used to construct fully human scFv and IgG with the biological functional activity that was predicted by deep sequencing.
Rick Wagner, Ph.D., Co-Founder and Chief Scientific Officer, X-Body BioSciences
Technology Workshops
1:45
Recombinantly expressed antibody variable domains can provide valuable recognition elements for the rapid detection of biologicals. The functional affinity of these reagents can be enhanced by expression as multimers. A simple method to dimerize an scFv is to shorten its linker, which results in diabody formation. We evaluated the monomer and dimer forms of an scFv. Multimerization domains such as alkaline phosphatase or streptavidin core create high affinity homodimers or tetramers that can provide the enhanced affinity required for the detection of threat agents.
George Anderson, Ph.D., Research Chemist, Naval Research Laboratory
To overcome limitations in antibody stability and other physicochemical properties we have generated a new, fully human antibody platform. All H/L pairs which pose the frameworks for this library were preselected with respect to expression levels, thermostability and aggregation propensity and great care was invested into the CDR design. In combination with the highly flexible arYla optimization technology this library constitutes an outstanding antibody platform to generate drug candidates with significantly improved developability and manufacturability.
Stefanie Urlinger, Ph.D., Director, MorphoSys AG, Germany
2:15
Announcements
Session II: 誘導形成結合部位的模式
2:20
Chairperson's Opening Remarks
James S. Huston, Ph.D., Chairman, The Antibody Society; Adjunct Scientist, Boston Biomedical Research Institute; Managing Member, Huston BioConsulting, LLC
Anthony Rees, MA DPhil DSc, Chief Scientific Officer, Biotage AB, Sweden
James S. Huston, Ph.D., Chairman, The Antibody Society; Adjunct Scientist, Boston Biomedical Research Institute; Managing Member, Huston BioConsulting, LLC
Anthony Rees, MA DPhil DSc, Chief Scientific Officer, Biotage AB, Sweden
2:30
Towards a Modular Protein-Sequence Specific Binding Code
Up to now, all recombinant and immunization strategies alike have required that binder selection for every single target is an independent "project". To work towards overcoming this limitation, we are developing a strategy towards a modular peptide-sequence recognition code. It is based on a combination of structure-guided, computational and evolutionary engineering of Armadillo Repeat Proteins. The development of this scaffold through several generations will be discussed.
Andreas Plückthun, Ph.D., Professor of Biochemistry, University of Zürich, Switzerland
Up to now, all recombinant and immunization strategies alike have required that binder selection for every single target is an independent "project". To work towards overcoming this limitation, we are developing a strategy towards a modular peptide-sequence recognition code. It is based on a combination of structure-guided, computational and evolutionary engineering of Armadillo Repeat Proteins. The development of this scaffold through several generations will be discussed.
Andreas Plückthun, Ph.D., Professor of Biochemistry, University of Zürich, Switzerland
3:00
Antibody Fragments Designed with Efficient Payloads for Cancer Diagnosis and Therapy
Antibody fragments (murine and human scFv and diabodies) were designed with unique surface disulphides for precise loading of either therapeutic-drug or radio-imaging payloads. With single-compound PEGylation, Tag72-targeting diabodies demonstrated remarkable xenograft-tumour uptake "( >70% ID/gm at 24hrs with fast blood clearance and low kidney (<10% ID/gm). Examples include PET-imaging with AVP04 diabody (an Avibody™ product) and an ADC (drug-loaded) therapeutic formulation. GMP-manufacture has exceeded 1gm/litre in bacterial fermentation and a Phase1 biodistribution (radioimaging) trial is imminent for prostate and ovarian cancer.
Peter J. Hudson, FTSE, Ph.D., Director, Victorian Cancer Biologics; Chief Scientific Officer, Avipep Pty Ltd., Australia
Antibody fragments (murine and human scFv and diabodies) were designed with unique surface disulphides for precise loading of either therapeutic-drug or radio-imaging payloads. With single-compound PEGylation, Tag72-targeting diabodies demonstrated remarkable xenograft-tumour uptake "( >70% ID/gm at 24hrs with fast blood clearance and low kidney (<10% ID/gm). Examples include PET-imaging with AVP04 diabody (an Avibody™ product) and an ADC (drug-loaded) therapeutic formulation. GMP-manufacture has exceeded 1gm/litre in bacterial fermentation and a Phase1 biodistribution (radioimaging) trial is imminent for prostate and ovarian cancer.
Peter J. Hudson, FTSE, Ph.D., Director, Victorian Cancer Biologics; Chief Scientific Officer, Avipep Pty Ltd., Australia
3:30
Structure Prediction of Fv and VHH Domains and Docking to their Antigens
We have developed high-resolution methods to predict the structure of antibodies and antibody-antigen complexes. The RosettaAntibody approach uses a database of antibody templates; ab initio construction of the CDR H3 loop; and simultaneous refinement of side chains, CDR loops, and relative VH-VL orientations. The SnugDock method for docking exploits the known antibody model uncertainties to enable successful docking of homology models. Recently we have extended the work to single-chain VHH domains utilizing conserved cysteine and loop distances to constrain the unusually long H3 loops.
Jeffrey J. Gray, Ph.D., Associate Professor, F. Stuart Hodgson Faculty Scholar, Chemical & Biomolecular Engineering, Johns Hopkins University
We have developed high-resolution methods to predict the structure of antibodies and antibody-antigen complexes. The RosettaAntibody approach uses a database of antibody templates; ab initio construction of the CDR H3 loop; and simultaneous refinement of side chains, CDR loops, and relative VH-VL orientations. The SnugDock method for docking exploits the known antibody model uncertainties to enable successful docking of homology models. Recently we have extended the work to single-chain VHH domains utilizing conserved cysteine and loop distances to constrain the unusually long H3 loops.
Jeffrey J. Gray, Ph.D., Associate Professor, F. Stuart Hodgson Faculty Scholar, Chemical & Biomolecular Engineering, Johns Hopkins University
4:00
Networking Refreshment Break
4:30
A New Clustering of Antibody CDR Loop Conformations for Structure Prediction and Design
Chothia's canonical clusters of antibody CDR structures are used extensively in antibody modeling and design. We have performed a new clustering with modern statistical methods, and developed an intuitive nomenclature for these clusters, e.g. L1-11-1 is CDR L1, length 11, and cluster 1. We analyzed 28 CDR-length combinations (e.g., L1-11), 15 of which had multiple conformational clusters. Approximately 85% of the non-H3 sequences can be assigned to a conformational cluster based on gene source and/or sequence. The analysis will be updated regularly as the structure database grows.
Roland L. Dunbrack, Jr., Ph.D., Associate Professor, Institute for Cancer Research Program in Molecular and Translational Medicine, Fox Chase Cancer Center
Chothia's canonical clusters of antibody CDR structures are used extensively in antibody modeling and design. We have performed a new clustering with modern statistical methods, and developed an intuitive nomenclature for these clusters, e.g. L1-11-1 is CDR L1, length 11, and cluster 1. We analyzed 28 CDR-length combinations (e.g., L1-11), 15 of which had multiple conformational clusters. Approximately 85% of the non-H3 sequences can be assigned to a conformational cluster based on gene source and/or sequence. The analysis will be updated regularly as the structure database grows.
Roland L. Dunbrack, Jr., Ph.D., Associate Professor, Institute for Cancer Research Program in Molecular and Translational Medicine, Fox Chase Cancer Center
5:00
Modeling the Complementarity Determining Regions in Antibodies: Structure and Dynamics
I will discuss our work on predicting antibody structure from sequence, focusing on the most challenging aspect, the H3 loop. In addition I will discuss related aspects of sequence-structure relationships in antibodies, including 1) the role of loop flexibility and its modulation by affinity maturation; 2) the energy landscape of the other 5 CDR loops; and 3) the relative orientations of the heavy and light chain variable domains.
Matthew P. Jacobson, Ph.D., Professor and Vice Chair, Department of Pharmaceutical Chemistry, University of California, San Francisco
I will discuss our work on predicting antibody structure from sequence, focusing on the most challenging aspect, the H3 loop. In addition I will discuss related aspects of sequence-structure relationships in antibodies, including 1) the role of loop flexibility and its modulation by affinity maturation; 2) the energy landscape of the other 5 CDR loops; and 3) the relative orientations of the heavy and light chain variable domains.
Matthew P. Jacobson, Ph.D., Professor and Vice Chair, Department of Pharmaceutical Chemistry, University of California, San Francisco
5:30
Computational Design of Protein-Protein Interactions
We have used iterative sequence optimization and docking with the molecular modeling program Rosetta to design a variety of protein-protein interactions. In each case, the designs are based on structural features found at naturally occurring interfaces, including beta-strand pairing, metal binding, and loop-mediated interactions. Sequence optimization simulations have also been used to design directed libraries that are enriched in sequences that bind a pre-specified target protein.
Brian Kuhlman, Ph.D., Associate Professor, Biochemistry and Biophysics, University of North Carolina
We have used iterative sequence optimization and docking with the molecular modeling program Rosetta to design a variety of protein-protein interactions. In each case, the designs are based on structural features found at naturally occurring interfaces, including beta-strand pairing, metal binding, and loop-mediated interactions. Sequence optimization simulations have also been used to design directed libraries that are enriched in sequences that bind a pre-specified target protein.
Brian Kuhlman, Ph.D., Associate Professor, Biochemistry and Biophysics, University of North Carolina
6:00
Networking Cocktail Reception; Opening of Poster and Exhibit Hall
Workshop: Sunday | Main Conference: Monday | Tuesday | Wednesday | Thursday
7:00
Registration, Networking Coffee
7:45
Announcements
Session III: 新的選定策略
7:50
Chairperson's Opening Remarks
James D. Marks, M.D., Ph.D., Professor and Vice Chairman, Anesthesia and Perioperative Care, University of California, San Francisco; Chief of Anesthesia, San Francisco General Hospital
James D. Marks, M.D., Ph.D., Professor and Vice Chairman, Anesthesia and Perioperative Care, University of California, San Francisco; Chief of Anesthesia, San Francisco General Hospital
8:00
Selection of Internalizing Phage Antibodies Using Tumor Cells and Yeast Displayed Tumor Antigens
Antibodies that bind cancer cells and are internalized can be used for tumor targeted drug and nucleic acid delivery. We show that such antibodies to specific tumor antigens can be generated by first selecting phage antibody libraries on a tumor cell line expressing the target antigen followed by selection on yeast displaying the same antigen on their surface. Advantages of this approach and specific examples will be covered.
James D. Marks, M.D., Ph.D., Professor and Vice Chairman, Anesthesia and Perioperative Care, University of California, San Francisco; Chief of Anesthesia, San Francisco General Hospital
Antibodies that bind cancer cells and are internalized can be used for tumor targeted drug and nucleic acid delivery. We show that such antibodies to specific tumor antigens can be generated by first selecting phage antibody libraries on a tumor cell line expressing the target antigen followed by selection on yeast displaying the same antigen on their surface. Advantages of this approach and specific examples will be covered.
James D. Marks, M.D., Ph.D., Professor and Vice Chairman, Anesthesia and Perioperative Care, University of California, San Francisco; Chief of Anesthesia, San Francisco General Hospital
8:30
Combining Phage and Yeast Display
Phage and yeast display have complementary capabilities. Phage antibody libraries have vast diversity, but selection is difficult to control. Selection on yeast, in contrast, is easy to control using flow cytometry, but large libraries are more difficult to manipulate. This talk will discuss the benefits of combining the two technologies.
Andrew Bradbury, M.D., Ph.D., Research Scientist and Team Leader, Los Alamos National Laboratories
Phage and yeast display have complementary capabilities. Phage antibody libraries have vast diversity, but selection is difficult to control. Selection on yeast, in contrast, is easy to control using flow cytometry, but large libraries are more difficult to manipulate. This talk will discuss the benefits of combining the two technologies.
Andrew Bradbury, M.D., Ph.D., Research Scientist and Team Leader, Los Alamos National Laboratories
9:00
Selecting Antibodies and Enzymes for Unique Selectivities and Activities
Protein display technologies are extremely powerful approaches for selection of naïve or improved binders to other macromolecules. We are designing more subtle properties using protein display, namely conformationally selective binders and a peptide ligase with improved activity. We have used chemical inhibitors to lock different conformations of caspases and used these as antigens for isolating, by differential selections, antibodies that function to activate or inhibit the enzyme. We have also developed a selection for improving a peptide ligase called subtiligase either by display on phage or yeast.
James A. Wells, Ph.D., Professor & Chair, Department of Pharmaceutical Chemistry, University of California San Francisco
Protein display technologies are extremely powerful approaches for selection of naïve or improved binders to other macromolecules. We are designing more subtle properties using protein display, namely conformationally selective binders and a peptide ligase with improved activity. We have used chemical inhibitors to lock different conformations of caspases and used these as antigens for isolating, by differential selections, antibodies that function to activate or inhibit the enzyme. We have also developed a selection for improving a peptide ligase called subtiligase either by display on phage or yeast.
James A. Wells, Ph.D., Professor & Chair, Department of Pharmaceutical Chemistry, University of California San Francisco
9:30
Networking Refreshment Break, Exhibit and Poster Viewing
10:15
Yeast Display for Identification and Engineering of Antibodies Against Membrane Protein Targets
Membrane proteins are challenging to work with in terms of antibody selection, engineering, and antigen identification as a result of their insolubility in aqueous solutions. We have therefore developed a platform for antibody engineering using either whole cells or cell lysates as antigen sources. Such approaches are compatible with membrane protein targets, subcellular selections, and the rapid assessment of antibody specificity. Moreover, when combined with yeast display immunoprecipitation procedures, antigen analysis is facilitated.
Eric V. Shusta, Ph.D., Associate Professor, Chemical and Biological Engineering, University of Wisconsin-Madison
Membrane proteins are challenging to work with in terms of antibody selection, engineering, and antigen identification as a result of their insolubility in aqueous solutions. We have therefore developed a platform for antibody engineering using either whole cells or cell lysates as antigen sources. Such approaches are compatible with membrane protein targets, subcellular selections, and the rapid assessment of antibody specificity. Moreover, when combined with yeast display immunoprecipitation procedures, antigen analysis is facilitated.
Eric V. Shusta, Ph.D., Associate Professor, Chemical and Biological Engineering, University of Wisconsin-Madison
10:45
CLIPS Technology Meets GPCR: A New Peptide Based Strategy for the Generation of Monoclonal Antibodies against GPCRs
CLIPS technology allows protein mimicry by design and synthesis of conformationally stabilized peptides with a well-defined 3D spatial structure, resembling the native functional protein surface. I will present data demonstrating the proof-of-principle that Pepscan's synthetic immunogens can induce antibodies against GPCR's and therefore are able to mimic the native receptor. Resulting antibodies do not bind only the native receptor, but also show functionality in different cell based in vitro assays.
Klaus Schwamborn, Ph.D., Chief Development Officer, Pepscan Therapeutics B.V., The Netherlands
CLIPS technology allows protein mimicry by design and synthesis of conformationally stabilized peptides with a well-defined 3D spatial structure, resembling the native functional protein surface. I will present data demonstrating the proof-of-principle that Pepscan's synthetic immunogens can induce antibodies against GPCR's and therefore are able to mimic the native receptor. Resulting antibodies do not bind only the native receptor, but also show functionality in different cell based in vitro assays.
Klaus Schwamborn, Ph.D., Chief Development Officer, Pepscan Therapeutics B.V., The Netherlands
11:15
In Vitro Antibody Selection Against Native Protein Conformations
The antibody phage display is a powerful approach to select rapidly and at low cost monoclonal antibodies. In the past, we have shown that it allows the efficient selection of conformation-specific antibodies. We have also shown that these antibodies can frequently be used as intrabodies to track the dynamics of their endogenous target. We are now exploring several approaches to improve the selection of antibodies directed against native protein conformation. This will represent unique tools both for fundamental and applied research.
Franck Perez, Ph.D., Group Leader and Research Director, Curie Institute, France
The antibody phage display is a powerful approach to select rapidly and at low cost monoclonal antibodies. In the past, we have shown that it allows the efficient selection of conformation-specific antibodies. We have also shown that these antibodies can frequently be used as intrabodies to track the dynamics of their endogenous target. We are now exploring several approaches to improve the selection of antibodies directed against native protein conformation. This will represent unique tools both for fundamental and applied research.
Franck Perez, Ph.D., Group Leader and Research Director, Curie Institute, France
Technology Workshops
11:45
Data from clinical studies show that one of the major issues with the use of therapeutic antibodies is the development of an anti-therapeutic antibody response. Such responses have been observed in many patients treated with anti-TNFα and α4β7-integrin antibodies for RA and IBS, as well as with antibodies and conjugates for various cancers. Data will be presented providing evidence linking the presence of T cell epitopes in the sequences of therapeutic antibodies with immunogenicity observed in patients as well as how antibodies can be engineered to avoid T cell epitopes.
Matthew Baker, Ph.D., Chief Scientific Officer, Co-Founder, Antitope Ltd
Fynomers represent a new class of binding molecules based on the human Fyn SH3 domain. We will provide examples of the broad applicability of the Fynomer technology, show novel Fynomer formats and present in vitro and in vivo data from our IL-17 program.
Speaker TBA, Covagen AG, Switzerland
Open Monoclonal Technology, Inc. ("OMT") is a private, California-based biotechnology company, that developed a fully human monoclonal antibody (mAb) platform based on transgenic rats. This new technology is the result of breakthroughs in the understanding of B-cell development and a novel approach to the inactivation of endogenous antibody expression. OMT's antibody platform has broad freedom to operate and uses technology protected by a new patent application.
Roland Buelow, Ph.D., Chief Executive Officer, Open Monoclonal Technology, Inc.
12:15
Networking Luncheon, Exhibit and Poster Viewing and NEW Antibody Platform Showcase
Technology Workshops
1:45
The ability to identify high affinity antibodies from Dyax's antibody phage display libraries has been demonstrated in over 70 selection campaigns, including dozens of therapeutic programs. The selection and screening of the library can be completed in days and the output of binders characterized in weeks. Here we will present a case study from Dyax's internal discovery pipeline that illustrates selection strategies and potency of the identified antibodies.
Andrew E. Nixon, Ph.D., Vice President, Lead Discovery & Biochemistry, Dyax
During antibody development, generation of high quality binding interaction data is essential for identifying antibodies with potential therapeutic use. However, many challenges can occur throughout the screening and characterization phase of development. Such challenges include the analyses of target antigen proteins with a propensity for nonspecific binding and the analyses of large numbers of unpurified antibody supernatant samples. Here, we will discuss how different label-free interaction analysis platforms are used to overcome these various challenges and how they can facilitate the identification and characterization of potential therapeutic antibodies.
Matthew C. Blome, Ph.D., Scientist, Therapeutic Proteins, Regeneron Pharmaceuticals, Inc.
κλ-Bodies are unmodified fully human bispecific IgGs. In contrast to existing engineered formats, κλ -Bodies are unique in offering the typical functional and biochemical characteristics of a human antibody. A streamlined platform approach for the identification, production and characterization of κλ -Bodies will be demonstrated.
Greg Elson, Head of Manufacturing, Novimmune SA, Switzerland
Session IV: 複合體環境下的抗體：細胞內的蛋白質及錯誤褶疊蛋白質的標的化
2:15
Chairperson's Opening Remarks
Richard H.J. Begent, M.D., Emeritus Professor of Oncology, UCL Cancer Institute, University College London, United Kingdom
Richard H.J. Begent, M.D., Emeritus Professor of Oncology, UCL Cancer Institute, University College London, United Kingdom
Session Keynote Presention
2:30
Gene and Antibody Therapies for Neurodegenerative Diseases Caused by Abnormal Protein Accumulation
Abnormal intracellular protein accumulations and interactions are critical mediators of a wide range of diseases. Neurons are especially vulnerable, given high metabolic demands and extreme longevity. Intrabodies offer a targeted proteomic approach to manipulating the conformations and intracellular localization of abnormal species for validation, direct therapeutics, and rational drug design. We have used a combination of antibody engineering and gene delivery to counteract pathogenic neurodegenerative phenotypes in culture and animal models.
Anne Messer, Ph.D., Professor and Senior Research Scientist, Molecular Genetics, Wadsworth Center, New York State Department of Health
Abnormal intracellular protein accumulations and interactions are critical mediators of a wide range of diseases. Neurons are especially vulnerable, given high metabolic demands and extreme longevity. Intrabodies offer a targeted proteomic approach to manipulating the conformations and intracellular localization of abnormal species for validation, direct therapeutics, and rational drug design. We have used a combination of antibody engineering and gene delivery to counteract pathogenic neurodegenerative phenotypes in culture and animal models.
Anne Messer, Ph.D., Professor and Senior Research Scientist, Molecular Genetics, Wadsworth Center, New York State Department of Health
3:15
Huntington's Disease - Developments in Intrabody Therapy
Huntington's disease is an autosomal dominant, neurodegenerative disease caused by the expansion of a polyglutamine repeat in the protein huntingtin (HTT). Gain of toxic function as a result of the mutation is thought to contribute to the complex disease process. The use of anti-HTT intrabodies that interfere with aberrant protein interactions, alter localization, or increase clearance of this toxic protein as a therapeutic strategy will be discussed.
Amber L. Southwell, Ph.D., Postdoctoral Researcher, University of British Columbia, Canada
Huntington's disease is an autosomal dominant, neurodegenerative disease caused by the expansion of a polyglutamine repeat in the protein huntingtin (HTT). Gain of toxic function as a result of the mutation is thought to contribute to the complex disease process. The use of anti-HTT intrabodies that interfere with aberrant protein interactions, alter localization, or increase clearance of this toxic protein as a therapeutic strategy will be discussed.
Amber L. Southwell, Ph.D., Postdoctoral Researcher, University of British Columbia, Canada
3:45
Immunity Proteins as Scaffolds for Stabilization of the Amyloid β Peptide
Alzheimer's Disease (AD) is a neurodegenerative disease thought to be caused by soluble, neurotoxic oligomers of the amyloid β peptide (Aβ). To overcome its aggregation we have trapped Aβ within protein scaffolds that exhibit high conformational tolerance, to stabilize the Aβ monomer and soluble oligomers. Using this technology we have successfully solved the crystal structure of the Aβ p3 fragment, which forms a novel dimeric structure. We are now utilizing the Aβ-scaffold proteins to develop conformational and region specific antibodies targeting Aβ.
Rebecca Nisbet, Ph.D., OCE Postdoctoral Fellow, CSIRO Materials Science and Engineering, Australia
Alzheimer's Disease (AD) is a neurodegenerative disease thought to be caused by soluble, neurotoxic oligomers of the amyloid β peptide (Aβ). To overcome its aggregation we have trapped Aβ within protein scaffolds that exhibit high conformational tolerance, to stabilize the Aβ monomer and soluble oligomers. Using this technology we have successfully solved the crystal structure of the Aβ p3 fragment, which forms a novel dimeric structure. We are now utilizing the Aβ-scaffold proteins to develop conformational and region specific antibodies targeting Aβ.
Rebecca Nisbet, Ph.D., OCE Postdoctoral Fellow, CSIRO Materials Science and Engineering, Australia
4:00
Networking Refreshment Break, Exhibit and Poster Viewing
4:45
Treatment of Amyloidosis with Antibodies to Human Serum Amyloid P Component
Accumulation of amyloid fibrils in the viscera causes systemic amyloi dosis. Amyloid deposits consist of the respective amyloid fibril protein and also contain serum amyloid P component (SAP). Current treatments, which can arrest amyloid accumulation, focus on substantially reducing the abundance of the amyloid fibril precursor protein, but this is not always possible. No therapy exists that enhances clearance of amyloid deposits. Administration of anti-human-SAP antibodies to amyloidotic mice swiftly removed massive visceral amyloid, and should be applicable to human amyloidosis.
Julian D. Gilmore, Ph.D., Senior Lecturer, National Amyloidosis Center, University College London Medical School, United Kingdom
Accumulation of amyloid fibrils in the viscera causes systemic amyloi dosis. Amyloid deposits consist of the respective amyloid fibril protein and also contain serum amyloid P component (SAP). Current treatments, which can arrest amyloid accumulation, focus on substantially reducing the abundance of the amyloid fibril precursor protein, but this is not always possible. No therapy exists that enhances clearance of amyloid deposits. Administration of anti-human-SAP antibodies to amyloidotic mice swiftly removed massive visceral amyloid, and should be applicable to human amyloidosis.
Julian D. Gilmore, Ph.D., Senior Lecturer, National Amyloidosis Center, University College London Medical School, United Kingdom
5:15
Engineering T cells with Antibody Based Chimeric Receptors: Preclinical and Early Clinical Results
Engineering T cells with antibody based chimeric receptors to target tumor associated antigens is a potentially general approach to treating malignant disease - these have been extensively optimized to produce efficient expression of functional, folded protein as an active receptor. Preclinical models suggest that the adoptive transfer of such engineered T cells is most effective when it follows chemotherapy as this greatly facilitates expansion and survival of the gene-modified cells. Based on preclinical models, trials targeting CD19 and CEA have been undertaken.
Robert E. Hawkins, Ph.D., Cancer Research UK Professor of Medical Oncology, University of Manchester, United Kingdom
Engineering T cells with antibody based chimeric receptors to target tumor associated antigens is a potentially general approach to treating malignant disease - these have been extensively optimized to produce efficient expression of functional, folded protein as an active receptor. Preclinical models suggest that the adoptive transfer of such engineered T cells is most effective when it follows chemotherapy as this greatly facilitates expansion and survival of the gene-modified cells. Based on preclinical models, trials targeting CD19 and CEA have been undertaken.
Robert E. Hawkins, Ph.D., Cancer Research UK Professor of Medical Oncology, University of Manchester, United Kingdom
5:45
Intranuclear Delivery of Radioimmunoconjugates that Target the DNA Repair Signaling Protein, γH2AX, for Imaging and Therapy of Cancer
DNA damage responses are induced by many anticancer drugs and by radiotherapy. A real-time method to image DNA damage in vivo would be useful to monitor treatment. Radiopharmaceuticals that target DNA damage signaling proteins could be used for treatment themselves, through amplification of pre-existing DNA damage. I will describe our work to develop fluorophore- and radioisotope-labeled immunoconjugates that target the DNA damage signaling protein, γH2AX, which forms foci at sites of DNA double-strand breaks.
Katherine Vallis, MBBS, Ph.D., Professor, Department of Oncology, University of Oxford, United Kingdom
DNA damage responses are induced by many anticancer drugs and by radiotherapy. A real-time method to image DNA damage in vivo would be useful to monitor treatment. Radiopharmaceuticals that target DNA damage signaling proteins could be used for treatment themselves, through amplification of pre-existing DNA damage. I will describe our work to develop fluorophore- and radioisotope-labeled immunoconjugates that target the DNA damage signaling protein, γH2AX, which forms foci at sites of DNA double-strand breaks.
Katherine Vallis, MBBS, Ph.D., Professor, Department of Oncology, University of Oxford, United Kingdom
6:15
Networking Cocktail Reception, Exhibit and Poster Viewing
Workshop: Sunday | Main Conference: Monday | Tuesday | Wednesday | Thursday
7:30
Registration, Networking Coffee
8:00
Announcements
Session V: 合理的疫苗設計
8:05
Chairperson's Opening Remarks
Dennis R. Burton, Ph.D., Professor, Department of Immunology and Microbial Science, The Scripps Research Institute
Dennis R. Burton, Ph.D., Professor, Department of Immunology and Microbial Science, The Scripps Research Institute
8:15
Engineering Effective Vaccine Antigens
Most current vaccines are based on antigens that are essentially the native macromolecules of pathogens. Using structural information, we can engineer antigens that are more stable, homogeneous, and efficiently produced, making immunization more practical and affordable. Understanding the structural basis for immunogenicity and immunodominance will allow us to improve vaccine efficacy and broaden the range of vaccine-preventable diseases. Examples that apply structural biology for the rational design of novel antigens will be presented.
Andrea Carfi, Ph.D., Head, Protein Biochemistry, USA, Novartis Vaccines & Diagnostics
Most current vaccines are based on antigens that are essentially the native macromolecules of pathogens. Using structural information, we can engineer antigens that are more stable, homogeneous, and efficiently produced, making immunization more practical and affordable. Understanding the structural basis for immunogenicity and immunodominance will allow us to improve vaccine efficacy and broaden the range of vaccine-preventable diseases. Examples that apply structural biology for the rational design of novel antigens will be presented.
Andrea Carfi, Ph.D., Head, Protein Biochemistry, USA, Novartis Vaccines & Diagnostics
8:45
Scaffolding Epitopes to Provide Directed Antibody Responses
Structure-guided approaches to vaccine design for a variety of pathogens have been enabled by structural information on epitopes targeted by neutralizing antibodies and by advances in computational design methods. In one approach - epitope scaffolding - epitopes are transplanted to scaffold proteins for conformational stabilization and exposure to the immune system. Biophysical, crystallographic, and immunologic results will be presented on scaffolds for selected epitopes from HIV and RSV.
William Schief, Ph.D., Principal Scientist, International AIDS Vaccine Initiative and Associate Professor of Immunology, The Scripps Research Institute
Structure-guided approaches to vaccine design for a variety of pathogens have been enabled by structural information on epitopes targeted by neutralizing antibodies and by advances in computational design methods. In one approach - epitope scaffolding - epitopes are transplanted to scaffold proteins for conformational stabilization and exposure to the immune system. Biophysical, crystallographic, and immunologic results will be presented on scaffolds for selected epitopes from HIV and RSV.
William Schief, Ph.D., Principal Scientist, International AIDS Vaccine Initiative and Associate Professor of Immunology, The Scripps Research Institute
9:15
Learning Immunology from Successful Vaccines: Innate Immunity to Systems Vaccinology
Despite their great success, we understand little about how effective vaccines stimulate protective immune responses. Two recent developments promise to yield such understanding: the appreciation of the crucial role of the innate immune system in sensing microorganisms and tuning immune responses, and advances in systems biology. In this presentation, I will discuss how these developments are yielding insights into the mechanism of some of the most successful vaccines ever developed, and the broader implications for vaccinology.
Bali Pulendran, Ph.D., Professor Pathology & Laboratory Medicine, Emory University
Despite their great success, we understand little about how effective vaccines stimulate protective immune responses. Two recent developments promise to yield such understanding: the appreciation of the crucial role of the innate immune system in sensing microorganisms and tuning immune responses, and advances in systems biology. In this presentation, I will discuss how these developments are yielding insights into the mechanism of some of the most successful vaccines ever developed, and the broader implications for vaccinology.
Bali Pulendran, Ph.D., Professor Pathology & Laboratory Medicine, Emory University
9:45
Networking Refreshment Break, Exhibit and Poster Viewing
10:30
Antibody Gene Delivery - A New Approach to Vaccines
The discovery of new and potent human monoclonal antibodies against a wide array of human pathogens has opened the door to a new form of immunoprophylaxis. Genes representing a given antibody (or combinations thereof) can be transferred to a naïve human subject wherein the gene directs production of the antibody in vivo. Thus, the gene recipient is endowed with the antibody specificity of the pre-selected molecule. The use of this approach for an HIV vaccine will be highlighted.
Philip R. Johnson, M.D., Chief Scientific Officer, The Children's Hospital of Philadelphia
The discovery of new and potent human monoclonal antibodies against a wide array of human pathogens has opened the door to a new form of immunoprophylaxis. Genes representing a given antibody (or combinations thereof) can be transferred to a naïve human subject wherein the gene directs production of the antibody in vivo. Thus, the gene recipient is endowed with the antibody specificity of the pre-selected molecule. The use of this approach for an HIV vaccine will be highlighted.
Philip R. Johnson, M.D., Chief Scientific Officer, The Children's Hospital of Philadelphia
11:00
Engineering Nanomaterials as Vaccine Adjuvants to Shape Humoral and Cellular Immunity
New nanomaterials for vaccine delivery will be described, based on classical liposome structures as well as a new class of lipid nanoparticles, interbilayer-crosslinked multilamellar vesicles (ICMVs). ICMVs are composed of multilamellar liposomes, stabilized by covalent crosslinks across bilayers within the vesicle walls. Using both model and disease (HIV and malaria) antigens, we demonstrate how the structure of these nanomaterials impacts the induction of follicular helper T-cell responses and subsequent humoral responses, leading to enhanced breadth of the antibody response against subunit antigens.
Darrell J. Irvine, Ph.D., Associate Professor, Biological Engineering, Materials Science & Engineering, Massachusetts Institute of Technology
New nanomaterials for vaccine delivery will be described, based on classical liposome structures as well as a new class of lipid nanoparticles, interbilayer-crosslinked multilamellar vesicles (ICMVs). ICMVs are composed of multilamellar liposomes, stabilized by covalent crosslinks across bilayers within the vesicle walls. Using both model and disease (HIV and malaria) antigens, we demonstrate how the structure of these nanomaterials impacts the induction of follicular helper T-cell responses and subsequent humoral responses, leading to enhanced breadth of the antibody response against subunit antigens.
Darrell J. Irvine, Ph.D., Associate Professor, Biological Engineering, Materials Science & Engineering, Massachusetts Institute of Technology
Special Presention
11:30
The Antibody Society
The Antibody Society (TAbS) was formed in 2007 to further the broad interests of the antibody engineering and antibody therapeutics community. This presentation will describe recent progress and initiatives for the coming year.
Jamie K. Scott, M.D., Ph.D., Professor, Dept. Molecular Biology, Biochemistry and Faculty of Health Sciences, Simon Fraser University, Canada
The Antibody Society (TAbS) was formed in 2007 to further the broad interests of the antibody engineering and antibody therapeutics community. This presentation will describe recent progress and initiatives for the coming year.
Jamie K. Scott, M.D., Ph.D., Professor, Dept. Molecular Biology, Biochemistry and Faculty of Health Sciences, Simon Fraser University, Canada
Technology Workshop
12:00
This abstract was not available at the time of printing the brochure.
Speaker TBA
12:30
Networking Luncheon, Last Chance for Exhibit and Poster Viewing
Session VI: 運用改變的結合分子使病毒（特別是腫瘤病毒）再標的化
2:00
Chairperson's Opening Remarks
Andrew Bradbury, M.D., Ph.D., Research Scientist and Team Leader, Los Alamos National Laboratories
Andrew Bradbury, M.D., Ph.D., Research Scientist and Team Leader, Los Alamos National Laboratories
2:15
Specific Gene Delivery to Cell Types of Choice by Cell Entry Targeted Lentiviral Vectors
Lentiviral vectors mediate stable and long-term transgene expression making them ideal gene delivery vehicles for research and therapy. Here we present a technology that enables cell type specific gene delivery by displaying single-chain antibodies on the vector envelope thereby restricting cell entry to antigen positive cells. Gene transfer with an unprecedented degree of specificity to endothelial cells, lymphocytes, neurons and tumor cells is demonstrated, not only ex vivo but also in vivo upon local or systemic application.
Christian Buchholz, Ph.D., Section Head, Professor of Biochemistry, Division of Medical Biotechnology, Paul-Ehrlich Institute, Germany
Lentiviral vectors mediate stable and long-term transgene expression making them ideal gene delivery vehicles for research and therapy. Here we present a technology that enables cell type specific gene delivery by displaying single-chain antibodies on the vector envelope thereby restricting cell entry to antigen positive cells. Gene transfer with an unprecedented degree of specificity to endothelial cells, lymphocytes, neurons and tumor cells is demonstrated, not only ex vivo but also in vivo upon local or systemic application.
Christian Buchholz, Ph.D., Section Head, Professor of Biochemistry, Division of Medical Biotechnology, Paul-Ehrlich Institute, Germany
2:45
Retargeting of Adenovirus Vectors through Genetic Fusion of a Single-chain or Single-domain Antibody to Capsid Protein IX
Adenovirus (Ad)-based vectors are widely used to deliver therapeutic genes to a variety of cell types and tissues. To target viral infection specifically to cancer cells, we investigated the Ad capsid protein IX (pIX) as a platform for addition of single-chain and single-domain antibodies directed towards cell surface antigens. We show that fusion of such molecules to pIX can enhance Ad infection of cancer cells, which should improve Ads safety and efficacy for cancer gene therapy.
Robin J. Parks, Ph.D., Senior Scientist, Regenerative Medicine Program, Ottawa Hospital Research Institute, Canada
Adenovirus (Ad)-based vectors are widely used to deliver therapeutic genes to a variety of cell types and tissues. To target viral infection specifically to cancer cells, we investigated the Ad capsid protein IX (pIX) as a platform for addition of single-chain and single-domain antibodies directed towards cell surface antigens. We show that fusion of such molecules to pIX can enhance Ad infection of cancer cells, which should improve Ads safety and efficacy for cancer gene therapy.
Robin J. Parks, Ph.D., Senior Scientist, Regenerative Medicine Program, Ottawa Hospital Research Institute, Canada
3:15
Antibody-Targeting with Added Value: Measles Virus
Measles is a simple (six genes) enveloped RNA virus that can be re-targeted by adding single-chain antibodies to its de-targeted attachment protein. Viral particles, lacking icosahedral symmetry, have variable cargo volume. Thus genes added for tracking or arming are well tolerated. Measles virus uses immune cells to move through the body, and hijacks a junction protein to transit through epithelial barriers. The use of armed, replicating measles viruses for targeted elimination of different tumors will be discussed.
Roberto Cattaneo, Ph.D., Professor of Biochemistry and Molecular Biology, Department of Molecular Medicine, Mayo Clinic
Measles is a simple (six genes) enveloped RNA virus that can be re-targeted by adding single-chain antibodies to its de-targeted attachment protein. Viral particles, lacking icosahedral symmetry, have variable cargo volume. Thus genes added for tracking or arming are well tolerated. Measles virus uses immune cells to move through the body, and hijacks a junction protein to transit through epithelial barriers. The use of armed, replicating measles viruses for targeted elimination of different tumors will be discussed.
Roberto Cattaneo, Ph.D., Professor of Biochemistry and Molecular Biology, Department of Molecular Medicine, Mayo Clinic
3:45
Networking Refreshment Break
4:15
Antibody Display on Enveloped Viruses
The high structural fidelity of antibodies displayed on enveloped viruses may be of considerable value, both for the generation of viruses with unique tropisms, and to facilitate in vivo antibody selection and affinity optimization. While single chain antibodies have been successfully displayed on the envelope glycoproteins of several widely differing mammalian viruses, only in the case of the measles H glycoprotein have displayed antibodies been shown capable of redirecting membrane fusion through a broad range of surrogate cell surface receptors. Applications will be discussed.
Stephen J. Russell, M.D., Ph.D., Professor of Medicine, Mayo Clinic
The high structural fidelity of antibodies displayed on enveloped viruses may be of considerable value, both for the generation of viruses with unique tropisms, and to facilitate in vivo antibody selection and affinity optimization. While single chain antibodies have been successfully displayed on the envelope glycoproteins of several widely differing mammalian viruses, only in the case of the measles H glycoprotein have displayed antibodies been shown capable of redirecting membrane fusion through a broad range of surrogate cell surface receptors. Applications will be discussed.
Stephen J. Russell, M.D., Ph.D., Professor of Medicine, Mayo Clinic
4:45
Candidate Oncolytic Herpes Simplex Viruses Retargeted to HER-2 and other Tumor-Specific Receptors by Means of Single Chain Antibodies
The onco-HSVs now in clinical trials are highly attenuated. Next generation onco-HSVs carry the genetic insertion of ligands to tumor-specific receptors in glycoprotein D (gD), the receptor-binding glycoprotein. The targeted receptor has been HER-2, overexpressed in ovary and mammary tumors. The inserted ligand has been a single chain antibody. Two privileged sites for insertion in gD were identified. The HER-2 retargeted onco-HSVs exert antitumor activity when administered intratumorally or systemically. The devised technology can target other receptors with available high affinity single chain antibodies.
Gabriella Campadelli Fiume, Ph.D., Professor of Microbiology and Virology, University of Bologna, Italy
The onco-HSVs now in clinical trials are highly attenuated. Next generation onco-HSVs carry the genetic insertion of ligands to tumor-specific receptors in glycoprotein D (gD), the receptor-binding glycoprotein. The targeted receptor has been HER-2, overexpressed in ovary and mammary tumors. The inserted ligand has been a single chain antibody. Two privileged sites for insertion in gD were identified. The HER-2 retargeted onco-HSVs exert antitumor activity when administered intratumorally or systemically. The devised technology can target other receptors with available high affinity single chain antibodies.
Gabriella Campadelli Fiume, Ph.D., Professor of Microbiology and Virology, University of Bologna, Italy
5:15
Generation of Bispecific DARPin Adapters for Efficient Adenoviral Gene Transfer
We developed a bispecific adapter strategy based on the DARPin scaffold that redirects Adenovirus serotype 5 (Ad5) to any target cell of choice. DARPins binding the Ad5 trimeric knob with nanomolar affinity were selected by ribosome display. Based on the crystal structure of the knob-DARPin complex and computer modeling, trivalent knob binders were generated. When fused to a DARPin recognizing HER2, the resulting trimeric, bispecific adapter enabled Ad5 virions deliver a luciferase reporter gene in a HER2-dependent manner.
Birgit Dreier, Ph.D., Senior Scientist, Department of Biochemistry, University of Zurich, Switzerland
We developed a bispecific adapter strategy based on the DARPin scaffold that redirects Adenovirus serotype 5 (Ad5) to any target cell of choice. DARPins binding the Ad5 trimeric knob with nanomolar affinity were selected by ribosome display. Based on the crystal structure of the knob-DARPin complex and computer modeling, trivalent knob binders were generated. When fused to a DARPin recognizing HER2, the resulting trimeric, bispecific adapter enabled Ad5 virions deliver a luciferase reporter gene in a HER2-dependent manner.
Birgit Dreier, Ph.D., Senior Scientist, Department of Biochemistry, University of Zurich, Switzerland
5:45
Close of Session
Workshop: Sunday | Main Conference: Monday | Tuesday | Wednesday | Thursday
7:30
Networking Coffee
8:00
Announcements
Session VII: 成為有力的暢銷藥物候選抗體之背景的生物學
8:05
Chairperson's Opening Remarks
Ian M. Tomlinson, Ph.D., Senior Vice President, Biopharmaceuticals R & D, GlaxoSmithKline, United Kingdom
Ian M. Tomlinson, Ph.D., Senior Vice President, Biopharmaceuticals R & D, GlaxoSmithKline, United Kingdom
8:15
Who'd Have Guessed that Hitting TNF Would Create a $10bn Market in Rheumatoid Arthritis
This abstract was not available at the time of printing the brochure.
Jochen G. Salfeld, Ph.D., Divisional Vice President Biologics, Distinguished Research Fellow, Abbott Bioresearch Center
This abstract was not available at the time of printing the brochure.
Jochen G. Salfeld, Ph.D., Divisional Vice President Biologics, Distinguished Research Fellow, Abbott Bioresearch Center
8:45
Is Anti-IL-12/23 the New Anti-TNF?
Ustekinumab is a human mAb that binds the shared p40 subunit of IL-12 and IL-23, resulting in the blockade of Th1 and Th17 inflammatory pathways. Ustekinumab is approved for the treatment of moderate-to-severe plaque psoriasis. Phase 2 studies demonstrated efficacy in Crohn's disease and psoriatic arthritis with no safety issues identified. Targeting both Th1 and Th17 cells via ustekinumab may provide new therapeutic options for patients with immune-mediated inflammatory diseases.
Kim A Campbell, Ph.D., Director, Immunology Product Support, Centocor Research & Development, a division of Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Ustekinumab is a human mAb that binds the shared p40 subunit of IL-12 and IL-23, resulting in the blockade of Th1 and Th17 inflammatory pathways. Ustekinumab is approved for the treatment of moderate-to-severe plaque psoriasis. Phase 2 studies demonstrated efficacy in Crohn's disease and psoriatic arthritis with no safety issues identified. Targeting both Th1 and Th17 cells via ustekinumab may provide new therapeutic options for patients with immune-mediated inflammatory diseases.
Kim A Campbell, Ph.D., Director, Immunology Product Support, Centocor Research & Development, a division of Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
9:15
IL-6 Signaling: Hit the Receptor, the Ligand or Both; The Pros and Cons
Treatment of autoimmune diseases with the anti-IL-6 receptor antibody Tocilizumab has underlined the importance of cytokines of the gp130 family. Disease progression by gp130 signaling and the special role of IL-6 with an emphasis on the role of the soluble IL-6 receptor in pro-inflammatory activities of this cytokine will be discussed. An overview will be given of preclinical and clinical blockade of IL-6 activity in autoimmunity, inflammation and cancer.
Stefan Rose-John, Ph.D., Professor of Biochemistry and Director, Department of Biochemistry, University of Kiel, Germany
Treatment of autoimmune diseases with the anti-IL-6 receptor antibody Tocilizumab has underlined the importance of cytokines of the gp130 family. Disease progression by gp130 signaling and the special role of IL-6 with an emphasis on the role of the soluble IL-6 receptor in pro-inflammatory activities of this cytokine will be discussed. An overview will be given of preclinical and clinical blockade of IL-6 activity in autoimmunity, inflammation and cancer.
Stefan Rose-John, Ph.D., Professor of Biochemistry and Director, Department of Biochemistry, University of Kiel, Germany
9:45
Networking Refreshment Break
10:15
Belimumab: A Human Monoclonal Antibody Against BLyS for the Treatment of SLE
For the first time in more than 50 years, a drug has been approved specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab (Benlysta®), is a monoclonal antibody that neutralizes the B cell survival factor, B lymphocyte stimulator (BLyS). The discovery of BLyS, its role in B cell biology and the effect of antagonizing BLyS in preclinical and clinical studies, with emphasis on B cells and biomarkers, will be discussed.
Thi-Sau Migone, Ph.D., Vice President, Research, Human Genome Sciences, Inc.
For the first time in more than 50 years, a drug has been approved specifically for the treatment of systemic lupus erythematosus (SLE). This drug, belimumab (Benlysta®), is a monoclonal antibody that neutralizes the B cell survival factor, B lymphocyte stimulator (BLyS). The discovery of BLyS, its role in B cell biology and the effect of antagonizing BLyS in preclinical and clinical studies, with emphasis on B cells and biomarkers, will be discussed.
Thi-Sau Migone, Ph.D., Vice President, Research, Human Genome Sciences, Inc.
10:45
What Does Anti-VEGF Therapy Actually do in the Tumor Vasculature?
This abstract was not available at the time of printing the brochure.
Gavin Thurston, Ph.D., Executive Director, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals
This abstract was not available at the time of printing the brochure.
Gavin Thurston, Ph.D., Executive Director, Oncology and Angiogenesis Research, Regeneron Pharmaceuticals
11:15
Dissecting the Biology of Bone to go Beyond Bisphosphonates; The Biology Behind Hitting the RANK Ligand
This abstract was not available at the time of printing the brochure.
David Lacey, M.D., Senior Vice President, Head of Research, Amgen, Inc.
This abstract was not available at the time of printing the brochure.
David Lacey, M.D., Senior Vice President, Head of Research, Amgen, Inc.
11:45
Lunch on Your Own
1:15
Announcements
Session VIII: 作為信號傳達修飾因子之機能抗體：能學習研究正確的方向性及迄今的成果
1:20
Chairperson's Opening Remarks
Louis M. Weiner, M.D., Director, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Louis M. Weiner, M.D., Director, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
1:30
Antibody Therapy of Cancer: Where did we go Right, and Where Do We Go From Here?
Unconjugated antibody-targeted therapeutics have emerged as vital components of the therapeutic armamentarium for cancers. Anti-cancer antibodies may work through a variety of mechanisms, including direct signaling effects and immunological effects, but the relative contributions of these mechanisms remains uncertain. We have previously identified conditions for enhancing the anti-tumor effects of antibodies by modifying the molecular structures of human IgG proteins. We describe strategies and results employing functional genomics techniques to identify the tumor cell-based molecular determinants of responsiveness to either signaling perturbation or antibody-dependent cellular cytotoxicity.
Louis M. Weiner, M.D., Director, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Unconjugated antibody-targeted therapeutics have emerged as vital components of the therapeutic armamentarium for cancers. Anti-cancer antibodies may work through a variety of mechanisms, including direct signaling effects and immunological effects, but the relative contributions of these mechanisms remains uncertain. We have previously identified conditions for enhancing the anti-tumor effects of antibodies by modifying the molecular structures of human IgG proteins. We describe strategies and results employing functional genomics techniques to identify the tumor cell-based molecular determinants of responsiveness to either signaling perturbation or antibody-dependent cellular cytotoxicity.
Louis M. Weiner, M.D., Director, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
2:00
Boosting the Delivery of Therapeutic Levels of Antibody to the Brain
Antibodies have a vast therapeutic potential for treatment of CNS diseases, but their passage into the brain is restricted by the blood-brain barrier (BBB). Here, we describe an approach to enhance receptor-mediated transcytosis pathways of brain endothelial cells to deliver therapeutically relevant dose levels of antibodies across the BBB.
Mark S. Dennis, M.S., Senior Scientist, Department of Antibody Engineering, Genentech, Inc.
Antibodies have a vast therapeutic potential for treatment of CNS diseases, but their passage into the brain is restricted by the blood-brain barrier (BBB). Here, we describe an approach to enhance receptor-mediated transcytosis pathways of brain endothelial cells to deliver therapeutically relevant dose levels of antibodies across the BBB.
Mark S. Dennis, M.S., Senior Scientist, Department of Antibody Engineering, Genentech, Inc.
2:30
Strategies for the Generation of Receptor Blocking Antibodies
Recombinant antibodies provide a means to control receptor activation with potential utility in the treatment of cancer or the control of stem cell differentiation. Using phage display in conjunction with cell based screening assays we have generated and affinity matured human antibodies which affect cell signaling by a number of different modalities including ligand neutralization, receptor blocking, signal processing and stabilization of closed conformations. The different approaches used will be discussed.
John McCafferty, Ph.D., Professor, Biochemistry, Cambridge University, United Kingdom
Recombinant antibodies provide a means to control receptor activation with potential utility in the treatment of cancer or the control of stem cell differentiation. Using phage display in conjunction with cell based screening assays we have generated and affinity matured human antibodies which affect cell signaling by a number of different modalities including ligand neutralization, receptor blocking, signal processing and stabilization of closed conformations. The different approaches used will be discussed.
John McCafferty, Ph.D., Professor, Biochemistry, Cambridge University, United Kingdom
3:00
Networking Refreshment Break
3:15
First-in-Class EGFR mAb Mixture, Sym004: Phase I Trial in Patients with Refractory Advanced Solid Tumors
Sym004 is a recombinant antibody 1:1 mixture of two chimeric anti-EGFR mAbs, targeting two non-overlapping epitopes, which elicits superior cancer cell growth inhibition in preclinical models. Uniquely, Sym004 mediates cell surface receptor removal by triggering EGFR internalization and degradation. Results from the first-in-human multicenter trial evaluating safety and tolerability of multiple doses of Sym004 are reported. Sym004 is well tolerated with no unexpected toxicities and shows preliminary signs of clinical activity.
Amita Patnaik, M.D., FRCPC, Associate Director of Clinical Research, START Center for Cancer Care
Sym004 is a recombinant antibody 1:1 mixture of two chimeric anti-EGFR mAbs, targeting two non-overlapping epitopes, which elicits superior cancer cell growth inhibition in preclinical models. Uniquely, Sym004 mediates cell surface receptor removal by triggering EGFR internalization and degradation. Results from the first-in-human multicenter trial evaluating safety and tolerability of multiple doses of Sym004 are reported. Sym004 is well tolerated with no unexpected toxicities and shows preliminary signs of clinical activity.
Amita Patnaik, M.D., FRCPC, Associate Director of Clinical Research, START Center for Cancer Care
3:45
Next-Generation Tri-Epitopic Anti-EGFR Antibodies: Overcoming Resistance by Enhanced Clustering and Downregulation
A tri-epitopic anti-EGFR antibody containing binding sites against three epitopes is found to rapidly cluster EGFR and downregulate its surface levels. We have isolated Fn3-based binders against EGFR, and fusions of these Fn3 domains to cetuximab leads to a single agent that dramatically downregulates and inhibits EGFR in over 15 tumor lines tested. In particular, tumor lines that are KRAS mutant and/or BRAF mutant are found to be controlled by the tri-epitopic construct despite an absence of efficacy for cetuximab.
K. Dane Wittrup, Ph.D., C.P. Dubbs Professor of Chemical Engineering and Biological Engineering, Massachusetts Institute of Technology
A tri-epitopic anti-EGFR antibody containing binding sites against three epitopes is found to rapidly cluster EGFR and downregulate its surface levels. We have isolated Fn3-based binders against EGFR, and fusions of these Fn3 domains to cetuximab leads to a single agent that dramatically downregulates and inhibits EGFR in over 15 tumor lines tested. In particular, tumor lines that are KRAS mutant and/or BRAF mutant are found to be controlled by the tri-epitopic construct despite an absence of efficacy for cetuximab.
K. Dane Wittrup, Ph.D., C.P. Dubbs Professor of Chemical Engineering and Biological Engineering, Massachusetts Institute of Technology
4:15
Close of Meeting
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