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Antibody Engineering Agenda
12:00
Registration Opens
1:30
Announcements
Working with IMGT® and other Ab Sequence Databases
The quality and capabilities of sequence databases continue to improve - and these have become a valuable tool for academic and industry researchers working in the field of Antibody Engineering. Our workshop session uses IMGT®, the international ImMunoGeneTics information system® (databases and online tools) as an example and provides an overview of its capabilities and a set of hands-on exercises demonstrating its application in various types of research. The session concludes with four case studies demonstrating the use of sequence databases.
1:30
Co-Chairpersons' Opening Remarks
Jamie K. Scott, M.D., Ph.D., Professor and Canada Research Chair in Molecular Immunity, Department of Molecular Biology & Biochemistry, Simon Fraser University, Canada
Marie-Paule Lefranc, Ph.D., Professor, Montpellier University, The University Institute of France, CNRS Institute of Human Genetics, IMGT, France
Jamie K. Scott, M.D., Ph.D., Professor and Canada Research Chair in Molecular Immunity, Department of Molecular Biology & Biochemistry, Simon Fraser University, Canada
Marie-Paule Lefranc, Ph.D., Professor, Montpellier University, The University Institute of France, CNRS Institute of Human Genetics, IMGT, France
1:45
Overview of IMGT®, The International ImMunoGeneTics Information System®
The IMGT databases (IMGT/LIGM-DB, IMGT/3Dstructure-DB…) and IMGT online tools (IMGT/DomainGapAlign and IMGT/Collier-de-Perles for amino acid sequences; IMGT/V-QUEST for nucleotide sequences) provide a standardized way to compare immunoglobulin sequences. They allow the delimiting of the FR-IMGT and CDR-IMGT in the process of antibody humanization and engineering. These criteria, based on IMGT-ONTOLOGY, the first ontology in immunogenetics and immunoinformatics, have been used to build the novel antibody IMGT/2Dstructure-DB database for INN entries.
Marie-Paule Lefranc, Ph.D., Professor, Montpellier University, The University Institute of France, CNRS Institute of Human Genetics, IMGT, France
The IMGT databases (IMGT/LIGM-DB, IMGT/3Dstructure-DB…) and IMGT online tools (IMGT/DomainGapAlign and IMGT/Collier-de-Perles for amino acid sequences; IMGT/V-QUEST for nucleotide sequences) provide a standardized way to compare immunoglobulin sequences. They allow the delimiting of the FR-IMGT and CDR-IMGT in the process of antibody humanization and engineering. These criteria, based on IMGT-ONTOLOGY, the first ontology in immunogenetics and immunoinformatics, have been used to build the novel antibody IMGT/2Dstructure-DB database for INN entries.
Marie-Paule Lefranc, Ph.D., Professor, Montpellier University, The University Institute of France, CNRS Institute of Human Genetics, IMGT, France
2:00
Interactive Exercises - IMGT Database
Felix Breden, Ph.D., Professor, Department of Biological Sciences, Simon Fraser University, Canada
Marie-Paule Lefranc, Ph.D., Professor, Montpellier University, The University Institute of France, CNRS Institute of Human Genetics, IMGT, France
Jamie K. Scott, M.D., Ph.D., Professor and Canada Research Chair in Molecular Immunity, Department of Molecular Biology & Biochemistry, Simon Fraser University, Canada
Felix Breden, Ph.D., Professor, Department of Biological Sciences, Simon Fraser University, Canada
Marie-Paule Lefranc, Ph.D., Professor, Montpellier University, The University Institute of France, CNRS Institute of Human Genetics, IMGT, France
Jamie K. Scott, M.D., Ph.D., Professor and Canada Research Chair in Molecular Immunity, Department of Molecular Biology & Biochemistry, Simon Fraser University, Canada
2:45
Repertoire Analysis of Allergen-Specific IgE Defines the Molecular Character of Allergy-Causing Immunoglobulins
Antibodies of the IgE isotype are key components of allergic immune responses. The low abundance of IgE-producing B lymphocytes has prevented efficient molecular characterization of such antibodies. Recently combinatorial library technology and phage display has been exploited as a tool to isolate and characterize allergen-specific antibodies derived from IgE-encoding transcriptome. In this presentation, I will discuss how we have used antibody sequence databases to assess the immunoglobulin repertoire targeting major protein allergens.
Mats Ohlin, Ph.D., Professor, Immunotechnology, Lund University, Sweden
Antibodies of the IgE isotype are key components of allergic immune responses. The low abundance of IgE-producing B lymphocytes has prevented efficient molecular characterization of such antibodies. Recently combinatorial library technology and phage display has been exploited as a tool to isolate and characterize allergen-specific antibodies derived from IgE-encoding transcriptome. In this presentation, I will discuss how we have used antibody sequence databases to assess the immunoglobulin repertoire targeting major protein allergens.
Mats Ohlin, Ph.D., Professor, Immunotechnology, Lund University, Sweden
3:15
Networking Refreshment Break
3:45
Structure-Function Relationships of Human mAbs with Polysaccharide Binding Activity from Natural and Adaptive Repertoires
We have analyzed the structure-function relationships of human mAbs with pneumococcal polysaccharide binding activity. The IgM mAbs were characteristic of natural antibodies with germline VDJ gene use, long CDR3, the selective use of Dh6 and Jh6 genes and broad specificity. Class switched mAbs were highly mutated with distinct V gene usage, diverse CDR3 and a specificity profile consistent with an antigen selected adaptive response.
Helen Baxendale, MBBS, Ph.D., Senior Lecturer and Honorary Consultant, Immunology, Royal Free Hospital and University College Medical School, United Kingdom
We have analyzed the structure-function relationships of human mAbs with pneumococcal polysaccharide binding activity. The IgM mAbs were characteristic of natural antibodies with germline VDJ gene use, long CDR3, the selective use of Dh6 and Jh6 genes and broad specificity. Class switched mAbs were highly mutated with distinct V gene usage, diverse CDR3 and a specificity profile consistent with an antigen selected adaptive response.
Helen Baxendale, MBBS, Ph.D., Senior Lecturer and Honorary Consultant, Immunology, Royal Free Hospital and University College Medical School, United Kingdom
4:15
Elucidating the Antigen Specificity of B Cells Present within Autoimmune Tissue and Solid Tumors
The immunoglobulin (Ig) sequences of B cells present in many autoimmune tissues and solid tumors exhibit clear evidence of antigen experience, yet the driving antigen(s) remain unknown. To identify these target antigens, single B cells were isolated from tissue specimens using laser-assisted microdissection. Then Ig variable regions were amplified and whole recombinant human Ig was constructed from paired heavy and light chains. Antigen discovery efforts have yielded a number of novel candidate antigens.
Kevin C. O'Connor, Ph.D., Assistant Professor of Neurology, Harvard Medical School
The immunoglobulin (Ig) sequences of B cells present in many autoimmune tissues and solid tumors exhibit clear evidence of antigen experience, yet the driving antigen(s) remain unknown. To identify these target antigens, single B cells were isolated from tissue specimens using laser-assisted microdissection. Then Ig variable regions were amplified and whole recombinant human Ig was constructed from paired heavy and light chains. Antigen discovery efforts have yielded a number of novel candidate antigens.
Kevin C. O'Connor, Ph.D., Assistant Professor of Neurology, Harvard Medical School
4:45
Hallmarks of the Antibody Variable Gene Repertoire Associated with Checkpoints of Immune Tolerance
Characterization of antibody variable gene usage during B cell development and immunity has identified particular hallmarks that occur either prior to selection or in association with autoreactive B cells. Examples include highly restricted use of particular variable and junctional genes such as VH4-34, VH3-30, and the JH6 gene. Selection for CDR3 length and the presence of charged amino acid residues are also major determinants of B cell selection. Somatic hypermutation is also an important factor that may distinguish simple auto- or poly-reactive antibodies from pathogenic autoantibodies found in autoimmune conditions.
Patrick C. Wilson, Ph.D., Assistant Professor, Department of Medicine and Rheumatology, Knapp Center for Lupus and Immunology Research, Committee on Immunology, The University of Chicago
Characterization of antibody variable gene usage during B cell development and immunity has identified particular hallmarks that occur either prior to selection or in association with autoreactive B cells. Examples include highly restricted use of particular variable and junctional genes such as VH4-34, VH3-30, and the JH6 gene. Selection for CDR3 length and the presence of charged amino acid residues are also major determinants of B cell selection. Somatic hypermutation is also an important factor that may distinguish simple auto- or poly-reactive antibodies from pathogenic autoantibodies found in autoimmune conditions.
Patrick C. Wilson, Ph.D., Assistant Professor, Department of Medicine and Rheumatology, Knapp Center for Lupus and Immunology Research, Committee on Immunology, The University of Chicago
5:15
Audience Discussion: Databases and Tools for Antibody Engineering and Clinical Applications
5:45
Workshop Ends
Workshop: Sunday | Main Conference: Monday | Tuesday | Wednesday | Thursday
7:30
Registration, Networking Coffee
8:00
Announcements
Session I: Antibody Repertoires and Responses
8:15
Co-Chairperson's Opening Remarks and Keynote Introduction
Dennis R. Burton, Ph.D., Professor, Immunology Department, The Scripps Research Institute
Marie-Paule Lefranc, Ph.D., Professor, Montpellier University, The University Institute of France, CNRS Institute of Human Genetics, IMGT, France
Dennis R. Burton, Ph.D., Professor, Immunology Department, The Scripps Research Institute
Marie-Paule Lefranc, Ph.D., Professor, Montpellier University, The University Institute of France, CNRS Institute of Human Genetics, IMGT, France
Keynote Presentation
8:30
Human Antibodies in Immunity and ToleranceWe have developed a method for cloning of antibodies from single human B cells and used it to characterize the development of antibodies in the bone marrow and during immune responses to HIV. We find that the majority of newly arising human antibodies are highly poly-reactive and that these antibodies are removed from the B cell repertoire at distinct checkpoints in the bone marrow and the periphery. Similar techniques have been used to characterize the memory antibody repertoire in patients with high titers of broadly neutralizing serum antibodies to HIV.
Michel Nussenzweig M.D., Ph.D., Investigator, Howard Hughes Medical Institute, Sherman Fairchild Professor and Senior Physician, The Rockefeller University
9:30
Audience Questions
9:45
Networking Refreshment Break
10:15
The Repertoire of Activated Plasmablasts Provides a Mirror Image of Ongoing Human B Cell Responses
Vaccination and acute immune responses induce a rapid and massive burst of plasmablasts that are predominantly specific to ongoing immune responses. This response represents a rich source of fully human monoclonal antibodies and a direct reflection of the currently activated B cell repertoire. Analyses will be presented concerning new understanding of the role of plasmablasts in B cell immunity and insights into immune decline with age.
Patrick C. Wilson, Ph.D., Assistant Professor, Department of Medicine and Rheumatology, Knapp Center for Lupus and Immunology Research, Committee on Immunology, The University of Chicago
Vaccination and acute immune responses induce a rapid and massive burst of plasmablasts that are predominantly specific to ongoing immune responses. This response represents a rich source of fully human monoclonal antibodies and a direct reflection of the currently activated B cell repertoire. Analyses will be presented concerning new understanding of the role of plasmablasts in B cell immunity and insights into immune decline with age.
Patrick C. Wilson, Ph.D., Assistant Professor, Department of Medicine and Rheumatology, Knapp Center for Lupus and Immunology Research, Committee on Immunology, The University of Chicago
10:45
Molecular Determinants of Neutralizing Human Antibody Responses to Viruses
Investigation of the human antibody response to virus infections has been largely limited in the past to serologies with relatively little analysis of antigen-specific B cells at the molecular level. We present studies of the human response to a wide variety of pathogenic viruses including influenza, RSV, and HIV. The studies reveal interesting features of the molecular basis for virus neutralization.
James E. Crowe, Jr., M.D., Ingram Professor of Research, Vanderbilt Medical Center
Investigation of the human antibody response to virus infections has been largely limited in the past to serologies with relatively little analysis of antigen-specific B cells at the molecular level. We present studies of the human response to a wide variety of pathogenic viruses including influenza, RSV, and HIV. The studies reveal interesting features of the molecular basis for virus neutralization.
James E. Crowe, Jr., M.D., Ingram Professor of Research, Vanderbilt Medical Center
11:15
Spatially Addressed Germline Repertoires for Antibody Discovery
Spatially addressed combinatorial libraries of recombinant human germline Fabs have been created through synthetic biology and high throughput fermentation and purification. Creation and screening of the library allows immediate information on expression, cross-reactivity, and SAR. The Fab library has been screened in multiplex assays to identify several low affinity but specific binders to many therapeutic targets. These have been affinity matured through iterative mutational processes. This discovery platform could allow discovery of novel Fabs against difficult targets and is amenable to functional cell based screening.
Vaughn Smider, M.D., Ph.D., Founder, Fabrus, LLC; Assistant Professor, Molecular Biology, The Scripps Research Institute
Spatially addressed combinatorial libraries of recombinant human germline Fabs have been created through synthetic biology and high throughput fermentation and purification. Creation and screening of the library allows immediate information on expression, cross-reactivity, and SAR. The Fab library has been screened in multiplex assays to identify several low affinity but specific binders to many therapeutic targets. These have been affinity matured through iterative mutational processes. This discovery platform could allow discovery of novel Fabs against difficult targets and is amenable to functional cell based screening.
Vaughn Smider, M.D., Ph.D., Founder, Fabrus, LLC; Assistant Professor, Molecular Biology, The Scripps Research Institute
11:45
Lunch on Your Own
Technology Workshops
1:15
Binding of a therapeutic antibody to its target antigen alters the target's interactions with its biological partners to acheive the desired effect. The mechanism of action of therapeutic antibodies is elucidated at the molecular level using a variety of platforms, including surface plasmon resonance (BioRad ProteOn, GE Biacore) and kinetic exclusion assays (Sapidyne KinExA). Predictions based on biophysical characteristics are tested in cell-based functional assays, demonstrating that the molecular mechanism translates into effects on biological function. Examples will be presented to illustrate investigation of receptor/ligand blocking and the use of kinetic and affinity analyses to elucidate a novel mechanism of action of a therapeutic antibody.
Marina Roell, Associate Director, Molecular Interactions & Biophysics, XOMA
Fabrus has developed an antibody discovery platform using spatially addressed human germline repertoires. This talk will present how we incorporate Meso Scale Discovery's MULTI-SPOT® electrochemiluminescence technology to identify micro-molar affinity "hits" against target antigens within a small library. We will also show examples of affinity-maturation process we carried out with some of the weak binders using targeted mutagenesis, and demonstrate functional binding of these antibodies in a cell-based assay.
Helen Mao, Ph.D., Chief Scientific Officer, Fabrus LLC
1:45
Technology Workshops
IBC's Technology Workshops offer supplier and service companies the opportunity to present product and service offers directly to the audience at the conference. For more information on presenting a technology workshop at this meeting, please contact us. Two workshop slots are available in this time slot at the time of printing this brochure.
IBC's Technology Workshops offer supplier and service companies the opportunity to present product and service offers directly to the audience at the conference. For more information on presenting a technology workshop at this meeting, please contact us. Two workshop slots are available in this time slot at the time of printing this brochure.
2:15
Announcements
Session II: Bispecific Antibodies and Antibody Combinations: The How and the Why
2:20
Chairperson's Opening Remarks
James D. Marks M.D., Ph.D., Department of Anesthesia and Pharmaceutical Chemistry, Member, Comprehensive Cancer Center, University of California, San Francisco
James D. Marks M.D., Ph.D., Department of Anesthesia and Pharmaceutical Chemistry, Member, Comprehensive Cancer Center, University of California, San Francisco
2:30
Unnatural Amino Acids for Discovery of Novel Antibodies and Bispecific Immunoconjugates
We have developed methods to engineer unnatural amino acids into variable and constant regions of antibody Fab fragments. Constant region modification allows creation of a site-specific conjugation system that can be used to couple toxins, proteins, or other antibody fragments to one another in a well-controlled reaction to produce defined products. Unique immunotoxins and bivalent molecules have been produced and analyzed for activity in vitro and in vivo.
Vaughn Smider, M.D., Ph.D., Assistant Professor, Molecular Biology, The Scripps Research Institute
We have developed methods to engineer unnatural amino acids into variable and constant regions of antibody Fab fragments. Constant region modification allows creation of a site-specific conjugation system that can be used to couple toxins, proteins, or other antibody fragments to one another in a well-controlled reaction to produce defined products. Unique immunotoxins and bivalent molecules have been produced and analyzed for activity in vitro and in vivo.
Vaughn Smider, M.D., Ph.D., Assistant Professor, Molecular Biology, The Scripps Research Institute
3:00
Rationally Designed, Combinatorial Strategies for Inhibiting ErbB Signaling
Insights from computational modeling have guided Merrimack's development of ErbB therapeutic regiments. In one approach targeted at inhibiting ligand-induced activation of the pathway, we are using MM-121, a monoclonal anti-ErbB3 antibody, as a single agent or in combination with EGFR inhibitors. In a second approach, aimed at treating ErbB2/HER2-amplified malignancies, a bispecific antibody fusion protein, MM-111, binding ErbB2 and ErbB3 has been devised. The designs and rationales of these approaches will be presented.
Ulrik Nielsen, Ph.D., Chief Scientific Officer, Merrimack Pharmaceuticals
Insights from computational modeling have guided Merrimack's development of ErbB therapeutic regiments. In one approach targeted at inhibiting ligand-induced activation of the pathway, we are using MM-121, a monoclonal anti-ErbB3 antibody, as a single agent or in combination with EGFR inhibitors. In a second approach, aimed at treating ErbB2/HER2-amplified malignancies, a bispecific antibody fusion protein, MM-111, binding ErbB2 and ErbB3 has been devised. The designs and rationales of these approaches will be presented.
Ulrik Nielsen, Ph.D., Chief Scientific Officer, Merrimack Pharmaceuticals
Special Presentation
3:30
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 progress in the past year, including the institution of a society journal, website progress and the creation of a Board of Distinguished Advisors. Results of a recent survey on The Antibody Society will be presented within the context of future plans, which will be open to discussion.
Andrew Bradbury, M.B., B.S., Ph.D., Research Scientist, Los Alamos National Laboratories; President, 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 progress in the past year, including the institution of a society journal, website progress and the creation of a Board of Distinguished Advisors. Results of a recent survey on The Antibody Society will be presented within the context of future plans, which will be open to discussion.
Andrew Bradbury, M.B., B.S., Ph.D., Research Scientist, Los Alamos National Laboratories; President, The Antibody Society
4:00
Networking Refreshment Break
4:30
Antibody Combinations and Bispecific Antibodies Potently Neutralize Botulinum Neurotoxins
We have generated human monoclonal antibodies that neutralize botulinum neurotoxins. When individual mAb are combined, the potency of neutralization increases dramatically. Strategies to capture this potency in a single antibody based molecule will be described.
James D. Marks M.D., Ph.D., Department of Anesthesia and Pharmaceutical Chemistry, Member, Comprehensive Cancer Center, University of California, San Francisco
We have generated human monoclonal antibodies that neutralize botulinum neurotoxins. When individual mAb are combined, the potency of neutralization increases dramatically. Strategies to capture this potency in a single antibody based molecule will be described.
James D. Marks M.D., Ph.D., Department of Anesthesia and Pharmaceutical Chemistry, Member, Comprehensive Cancer Center, University of California, San Francisco
5:00
The Design and Engineering of Fc Heterodimers for the Production of Bispecific Antibodies and Other Heterodimer Fusion Proteins
We have modified the CH3 domain of the Fc interface with a few selected mutations so the engineered Fc proteins preferentially form heterodimers. Our engineering approach takes advantage of electrostatic interactions in promoting Fc heterodimer formation and discouraging Fc homodimers and does not affect the hydrophobic core of the CH3 domain interface. The successful production of heterodimeric Fc molecules facilitates the construction of bispecific antibodies and various heterodimeric Fc fusion proteins.
Wei Yan, Ph.D., Principal Scientist, Protein Science, Amgen Inc.
We have modified the CH3 domain of the Fc interface with a few selected mutations so the engineered Fc proteins preferentially form heterodimers. Our engineering approach takes advantage of electrostatic interactions in promoting Fc heterodimer formation and discouraging Fc homodimers and does not affect the hydrophobic core of the CH3 domain interface. The successful production of heterodimeric Fc molecules facilitates the construction of bispecific antibodies and various heterodimeric Fc fusion proteins.
Wei Yan, Ph.D., Principal Scientist, Protein Science, Amgen Inc.
5:30
Dual Variable Domain (DVD)-IgTM Technology: Some Technical Considerations in Constructing DVD-Ig Molecules
DVD-IgTM technology can convert any mono-specific mAb to a dual-targeting biologic. A DVD-Ig is constructed by attaching antigen-binding domain of one mAb on to another pre-existing mAb. This modular approach enables construction of multiple molecules simultaneously to determine contributions of various components of DVD-Ig to functional and physicochemical properties. New insights into making DVD-Ig will be discussed.
Tariq Ghayur, Ph.D., Senior Principal Scientist and Research Fellow, Abbott Bioresearch Center
DVD-IgTM technology can convert any mono-specific mAb to a dual-targeting biologic. A DVD-Ig is constructed by attaching antigen-binding domain of one mAb on to another pre-existing mAb. This modular approach enables construction of multiple molecules simultaneously to determine contributions of various components of DVD-Ig to functional and physicochemical properties. New insights into making DVD-Ig will be discussed.
Tariq Ghayur, Ph.D., Senior Principal Scientist and Research Fellow, Abbott Bioresearch Center
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: Antibodies in a Complex Environment
7:50
Chairperson's Opening Remarks
Richard H.J. Begent, M.D., Head of Oncology, Ronald Raven Professor of Oncology, University College London, United Kingdom
Richard H.J. Begent, M.D., Head of Oncology, Ronald Raven Professor of Oncology, University College London, United Kingdom
8:00
FcRn as an IgG Homeostat: from Single Molecules to In Vivo Function
FcRn is a key regulator of the distribution and pharmacokinetics of IgGs. Recent work in our laboratory has involved an analysis of FcRn function at both the subcellular and whole body levels, together with the development of engineered antibodies that inhibit FcRn function. Results from these studies will be presented.
E. Sally Ward, Ph.D., Professor of Immunology, University of Texas Southwestern Medical Center
FcRn is a key regulator of the distribution and pharmacokinetics of IgGs. Recent work in our laboratory has involved an analysis of FcRn function at both the subcellular and whole body levels, together with the development of engineered antibodies that inhibit FcRn function. Results from these studies will be presented.
E. Sally Ward, Ph.D., Professor of Immunology, University of Texas Southwestern Medical Center
8:30
A Systems Approach to Improving EGFR-Targeted Therapy
This abstract was not available at the time of printing the brochure.
Louis M. Weiner, M.D., Director, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
This abstract was not available at the time of printing the brochure.
Louis M. Weiner, M.D., Director, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
9:00
Addressing Tumor Complexity using Intra-Tumor Prodrug Activation
Intra-tumor prodrug activation by pre-targeted antibody-enzyme can be used to generate a potent cytotoxic in the tumor mass; essentially turning the tumor into a factory for its own destruction. The system has the potential to kill antigen negative cells, stem cells and tumor-supporting stroma; elements that may not be addressed by other antibody therapies. Feasibility and new developments of the system will be discussed using a bedside-to-bench approach.
Kerry A. Chester, Ph.D., Professor of Molecular Medicine, University College London, United Kingdom
Intra-tumor prodrug activation by pre-targeted antibody-enzyme can be used to generate a potent cytotoxic in the tumor mass; essentially turning the tumor into a factory for its own destruction. The system has the potential to kill antigen negative cells, stem cells and tumor-supporting stroma; elements that may not be addressed by other antibody therapies. Feasibility and new developments of the system will be discussed using a bedside-to-bench approach.
Kerry A. Chester, Ph.D., Professor of Molecular Medicine, University College London, United Kingdom
9:30
Networking Refreshment Break, Exhibit and Poster Viewing
10:15
Blocking Monoclonal Antibodies Directed Against CD47 Preferentially Enable Phagocytosis and Elimination of Human Acute Myeloid Leukemia Stem Cells
We identified increased expression of CD47 on human AML stem cells (LSC) and hypothesized that CD47 contributes to pathogenesis by inhibiting phagocytosis of these cells through its interaction with an inhibitory receptor on phagocytes. Blocking monoclonal antibodies directed against CD47 preferentially enabled phagocytosis of AML LSC and inhibited their engraftment in vivo. Furthermore, treatment of human AML LSC-engrafted mice with anti-CD47 antibody depleted AML and targeted LSC.
Ravindra Majeti M.D., Ph.D., Assistant Professor, Stanford Cancer Center, Division of Hematology, Stanford University
We identified increased expression of CD47 on human AML stem cells (LSC) and hypothesized that CD47 contributes to pathogenesis by inhibiting phagocytosis of these cells through its interaction with an inhibitory receptor on phagocytes. Blocking monoclonal antibodies directed against CD47 preferentially enabled phagocytosis of AML LSC and inhibited their engraftment in vivo. Furthermore, treatment of human AML LSC-engrafted mice with anti-CD47 antibody depleted AML and targeted LSC.
Ravindra Majeti M.D., Ph.D., Assistant Professor, Stanford Cancer Center, Division of Hematology, Stanford University
10:45
Human Antibodies and Host Immunity to Influenza A Hemagglutinin
Influenza virus entry into host cells requires a global change in conformation of its major surface protein, hemagglutinin (HA), which triggers the fusion of viral and host membranes. The nexus of this change resides in the membrane-proximal stem region, which lies beneath the highly immunogenic and variable receptor-binding head. The need to adopt two very different conformations places strong evolutionary constraints on the sequence of the stem. Neutralizing antibodies to this region will be discussed.
Wayne A. Marasco, M.D., Ph.D., Associate Professor of Medicine, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School; Scientific Director, National Foundation for Cancer Research (NFCR) - Center for Therapeutic Antibody Engineering (CTAE)
Influenza virus entry into host cells requires a global change in conformation of its major surface protein, hemagglutinin (HA), which triggers the fusion of viral and host membranes. The nexus of this change resides in the membrane-proximal stem region, which lies beneath the highly immunogenic and variable receptor-binding head. The need to adopt two very different conformations places strong evolutionary constraints on the sequence of the stem. Neutralizing antibodies to this region will be discussed.
Wayne A. Marasco, M.D., Ph.D., Associate Professor of Medicine, Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; Department of Medicine, Harvard Medical School; Scientific Director, National Foundation for Cancer Research (NFCR) - Center for Therapeutic Antibody Engineering (CTAE)
11:15
Recognition of the Influenza Virus Hemagglutinin by Neutralizing Antibodies
Current influenza vaccines provide protection only against viral isolates similar to the vaccine strain, and will likely prove ineffective against an emerging pandemic virus. In contrast, antibodies recognizing conserved epitopes in the major surface antigen, hemagglutinin, neutralize across multiple virus subtypes. Here we present structural and mechanistic data highlighting the interaction of several monoclonal antibodies with the hemagglutinin. Such antibodies have immediate clinical applications and should guide the design of improved vaccines that elicit similar, broadly neutralizing antibodies.
Damian C. Ekiert, Ph.D. Candidate, The Scripps Research Institute
Current influenza vaccines provide protection only against viral isolates similar to the vaccine strain, and will likely prove ineffective against an emerging pandemic virus. In contrast, antibodies recognizing conserved epitopes in the major surface antigen, hemagglutinin, neutralize across multiple virus subtypes. Here we present structural and mechanistic data highlighting the interaction of several monoclonal antibodies with the hemagglutinin. Such antibodies have immediate clinical applications and should guide the design of improved vaccines that elicit similar, broadly neutralizing antibodies.
Damian C. Ekiert, Ph.D. Candidate, The Scripps Research Institute
Technology Workshops
11:45
The clinical immunogenicity of biologics is typically associated with the development of high affinity IgG anti-therapeutic antibodies, indicating the role of CD4+ helper T cell epitopes. We have compared a number of technologies that enable the preclinical prediction of immunogenicity, and using EpiScreen™ technology, we have observed a correlation between T cell responses to biologics and the immunogenicity of protein therapeutics in the clinic. Data will be presented demonstrating our technology in screening for and removing immunogenicity from biologics.
Frank Carr, Ph.D., Director for Biologics Research, Antitope, United Kingdom
Integral Molecular's Lipoparticle technology provides an innovative solution for presenting structurally intact membrane protein antigens, including GPCRs and ion channels, at concentrations 10-100X higher (50-200 pmol/mg) than in cells or membrane preparations. This has enabled us to derive high titer serum responses (>1:500) against membrane proteins of interest. Once MAbs are isolated, our Shotgun Mutagenesis mapping technology has enabled us to rapidly identify both linear and conformationally complex epitopes that distinguish MAb binding sites.
Benjamin Doranz, Ph.D., President and Chief Scientific Officer, Integral Molecular
12:15
Networking Luncheon, Exhibit and Poster Viewing
Technology Workshop
1:45
Open Monoclonal Technology, Inc. (www.omtinc.net) is developing a human antibody platform using transgenic rats. This technology is based on an improved understanding of B-cell development and a novel approach to inactivating endogenous rat antibody expression. OMT's platform has broad freedom to operate and is protected by a patent application.
Roland Buelow, Ph.D., Chief Executive Officer, OMT Inc.
2:15
Announcements
Session IV: Antibodies - Not Just for Injection
2:20
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
2:30
Effective Delivery of Domain Antibodies to the Lung
Due to their small size and stability, human domain antibodies (dAbs) can readily be delivered to the respiratory tract. We have demonstrated superior efficacy using a low doses of pulmonary delivered dAb against the TNF receptor 1 in mouse models for COPD and acute inflammatory models in non-human primates. This data demonstrates utility of dAbs for pulmonary delivery and highlights the potential of TNFR1 as a target for treatment of pulmonary inflammatory diseases.
Amrik Basran, Ph.D., Director Discovery Biosciences, GlaxoSmithKline, United Kingdom
Due to their small size and stability, human domain antibodies (dAbs) can readily be delivered to the respiratory tract. We have demonstrated superior efficacy using a low doses of pulmonary delivered dAb against the TNF receptor 1 in mouse models for COPD and acute inflammatory models in non-human primates. This data demonstrates utility of dAbs for pulmonary delivery and highlights the potential of TNFR1 as a target for treatment of pulmonary inflammatory diseases.
Amrik Basran, Ph.D., Director Discovery Biosciences, GlaxoSmithKline, United Kingdom
3:00
Anticalins: New Options for Mode of Action and Administration
An Anticalin that neutralizes VEGF-A is about to enter the clinic as a potent inhibitor of tumor angiogenesis and also offers prospects for the treatment of disorders that require local application, e.g. in the eye or joints. Another antagonistic Anticalin directed against an immune cell receptor is in preclinical development for severe asthma and appears suitable for pulmonary delivery. Due to their small size and robust constitution Anticalins provide several benefits for alternative routes of administration.
Arne Skerra, Ph.D., Professor, Pieris AG and Technical University of Munich, Germany
An Anticalin that neutralizes VEGF-A is about to enter the clinic as a potent inhibitor of tumor angiogenesis and also offers prospects for the treatment of disorders that require local application, e.g. in the eye or joints. Another antagonistic Anticalin directed against an immune cell receptor is in preclinical development for severe asthma and appears suitable for pulmonary delivery. Due to their small size and robust constitution Anticalins provide several benefits for alternative routes of administration.
Arne Skerra, Ph.D., Professor, Pieris AG and Technical University of Munich, Germany
3:30
Alternative Delivery of Nanobodies®
Llama-derived Nanobodies have inherent biophysical properties, including small size (≥15kD), thermodynamic stability, resistance to pH and protease degradation, that make them ideal candidates for exploratory studies on alternative methods of drug delivery. We have been evaluating whether Nanobodies can be delivered via routes other than intravenous injection. Data will be presented demonstrating that Nanobodies can retain their function when delivered via skin (SC), oral and pulmonary routes.
Debbie Law, Ph.D., Chief Scientific Officer, Ablynx, Belgium
Llama-derived Nanobodies have inherent biophysical properties, including small size (≥15kD), thermodynamic stability, resistance to pH and protease degradation, that make them ideal candidates for exploratory studies on alternative methods of drug delivery. We have been evaluating whether Nanobodies can be delivered via routes other than intravenous injection. Data will be presented demonstrating that Nanobodies can retain their function when delivered via skin (SC), oral and pulmonary routes.
Debbie Law, Ph.D., Chief Scientific Officer, Ablynx, Belgium
4:00
Networking Refreshment Break, Exhibit and Poster Viewing
4:45
Accelerating scFv Antibody Fragments for Topical Applications into the Clinic
Single-chain antibody fragments qualify for local therapies and delivery routes that have not yet been explored for full-size antibodies and larger fragments thereof. ESBA105 is a humanized anti-TNF scFv, developed for the treatment of inflammatory ocular diseases as well as for osteoarthritis. This antibody fragment, upon administration by eye drops, penetrates into all ocular compartments and reaches therapeutic concentrations in the aequeous and the retina. Preclinical efficacy with topical application of eye drops containing ESBA105 is shown in the monkey laser-injury model for choroid neovascularisation.
David Urech, Ph.D., Head of Research & Development, ESBATech, Switzerland
Single-chain antibody fragments qualify for local therapies and delivery routes that have not yet been explored for full-size antibodies and larger fragments thereof. ESBA105 is a humanized anti-TNF scFv, developed for the treatment of inflammatory ocular diseases as well as for osteoarthritis. This antibody fragment, upon administration by eye drops, penetrates into all ocular compartments and reaches therapeutic concentrations in the aequeous and the retina. Preclinical efficacy with topical application of eye drops containing ESBA105 is shown in the monkey laser-injury model for choroid neovascularisation.
David Urech, Ph.D., Head of Research & Development, ESBATech, Switzerland
5:15
The Challenge of Ocular Drug Delivery For Small Molecules and Proteins
Age related macular degeneration (AMD) is the leading cause of blindness in the USA; with the development of anti VEGF antibodies the progression of AMD can be controlled and in some cases a gain vision can be achieved. The current delivery modality to get the anti VEGF antibodies to the target tissues (retina & choroid) is with monthly intravitreal injections. This presentation will discuss and compare ocular drug delivery of topical eye drops, transscleral diffusion, intrascleral and suprachoridal delivery with microneedles and the potential of using microbeads, nanoparticles and viscoelastics to achieve sustained release drug delivery of antibodies and small molecules
Henry F. Edelhauser, Ph.D., Professor of Ophthalmology, Emory University Eye Center
Age related macular degeneration (AMD) is the leading cause of blindness in the USA; with the development of anti VEGF antibodies the progression of AMD can be controlled and in some cases a gain vision can be achieved. The current delivery modality to get the anti VEGF antibodies to the target tissues (retina & choroid) is with monthly intravitreal injections. This presentation will discuss and compare ocular drug delivery of topical eye drops, transscleral diffusion, intrascleral and suprachoridal delivery with microneedles and the potential of using microbeads, nanoparticles and viscoelastics to achieve sustained release drug delivery of antibodies and small molecules
Henry F. Edelhauser, Ph.D., Professor of Ophthalmology, Emory University Eye Center
5:45
Induction of Regulatory T Cells by Mucosal Administration of Anti-CD3 Antibody Suppresses Autoimmunity
We investigated Treg induction in autoimmunity models and in humans by mucosal anti-CD3 antibody. The mucosal route preferentially induces tolerance. Parenteral anti-CD3 is efficacious in autoimmunity models and is FDA approved for transplant rejection. Oral anti-CD3 suppressed animal models (MS, T1D and T2D, lupus, colitis) and induced immune changes in humans with no toxicity. Results identify novel and physiologic mechanisms to induce Tregs that are clinically applicable to a variety of immune mediated disorders.
Howard L. Weiner, M.D., Professor, Center for Neurologic Diseases, Brigham and Women's Hospital
We investigated Treg induction in autoimmunity models and in humans by mucosal anti-CD3 antibody. The mucosal route preferentially induces tolerance. Parenteral anti-CD3 is efficacious in autoimmunity models and is FDA approved for transplant rejection. Oral anti-CD3 suppressed animal models (MS, T1D and T2D, lupus, colitis) and induced immune changes in humans with no toxicity. Results identify novel and physiologic mechanisms to induce Tregs that are clinically applicable to a variety of immune mediated disorders.
Howard L. Weiner, M.D., Professor, Center for Neurologic Diseases, Brigham and Women's Hospital
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: Antibody Polyspecificity and Single Molecule Imaging
8:05
Chairperson's Opening Remarks
Andrew Bradbury, M.B., B.S., Ph.D., Research Scientist, Los Alamos National Laboratories
Andrew Bradbury, M.B., B.S., Ph.D., Research Scientist, Los Alamos National Laboratories
8:15
Measuring an Antibody Affinity Distribution Molecule by Molecule with Single Molecule Imaging
Single molecule fluorescence microscopy was used to study the binding events of fluorescent antigens (biotinylated quantum dots) to individual surface immobilized (anti-biotin mouse IgG) antibodies. The fluorescence time history at an individual antibody location was monitored and used to calculate its binding affinity. By measuring individual affinities of a large population of antibodies, the surface affinity distribution function can be derived.
Jamshid Temirov, Ph.D., Senior Scientist, Genetic Systems, Life Technologies
Single molecule fluorescence microscopy was used to study the binding events of fluorescent antigens (biotinylated quantum dots) to individual surface immobilized (anti-biotin mouse IgG) antibodies. The fluorescence time history at an individual antibody location was monitored and used to calculate its binding affinity. By measuring individual affinities of a large population of antibodies, the surface affinity distribution function can be derived.
Jamshid Temirov, Ph.D., Senior Scientist, Genetic Systems, Life Technologies
8:45
Using Atomic Force Microscopy for Single Molecule Based Selection and Analysis of Antibody Interactions
Reagents that recognize specific protein morphologies can be used as diagnostic and therapeutic tools for treating protein misfolding diseases such as Alzheimer's disease. Using Atomic Force Microscopy to image both protein aggregation and the biopanning process, we can isolate antibody fragments to specific protein morphologies using minimal antigenic target, even as little as a single molecule. Antibody binding specificity can also be determined by AFM using only minimal target antigen.
Michael Sierks, Ph.D., Professor, Chemical Engineering, Arizona State University
Reagents that recognize specific protein morphologies can be used as diagnostic and therapeutic tools for treating protein misfolding diseases such as Alzheimer's disease. Using Atomic Force Microscopy to image both protein aggregation and the biopanning process, we can isolate antibody fragments to specific protein morphologies using minimal antigenic target, even as little as a single molecule. Antibody binding specificity can also be determined by AFM using only minimal target antigen.
Michael Sierks, Ph.D., Professor, Chemical Engineering, Arizona State University
9:15
How do the Paratopes of Antigen-Receptors Classify the Epitopic Universe?
The way we approach this question has ramifications both conceptual and empirical. There are two distinct sets of antigen-receptors, BCR and TCR, and there are two polar theories as to how each set classifies the epitopic universe. The role of the theories in understanding the two families of receptors as well as their relationship to effector function will be delineated.
Melvin Cohn, Ph.D., Professor, Conceptual Immunology Group, Salk Institute
The way we approach this question has ramifications both conceptual and empirical. There are two distinct sets of antigen-receptors, BCR and TCR, and there are two polar theories as to how each set classifies the epitopic universe. The role of the theories in understanding the two families of receptors as well as their relationship to effector function will be delineated.
Melvin Cohn, Ph.D., Professor, Conceptual Immunology Group, Salk Institute
9:45
Networking Refreshment Break, Exhibit and Poster Viewing
10:30
Specificity of Antigen Recognition in the Immune Response
Antigen recognition and subsequent affinity maturation interface physico-chemical principles of molecular interactions with the physiological processes associated with self-nonself discrimination. We have addressed antigen-antibody interaction in the context of breakdown in the antigenic discrimination, economy of the antibody conformational repertoire and generation of antibody diversity. These studies, applying thermodynamic and crystallographic approaches, have resulted in identification of intriguing new aspects of immune recognition with possibilities of novel applications.
Dinakar M. Salunke, Ph.D., Scientist, National Institute of Immunology, India
Antigen recognition and subsequent affinity maturation interface physico-chemical principles of molecular interactions with the physiological processes associated with self-nonself discrimination. We have addressed antigen-antibody interaction in the context of breakdown in the antigenic discrimination, economy of the antibody conformational repertoire and generation of antibody diversity. These studies, applying thermodynamic and crystallographic approaches, have resulted in identification of intriguing new aspects of immune recognition with possibilities of novel applications.
Dinakar M. Salunke, Ph.D., Scientist, National Institute of Immunology, India
11:00
Two-in-One Antibody: Herceptin Variants that also Bind VEGF with High Affinity
We explored the ability of an antigen-binding site to interact with two unrelated protein antigens using an engineering approach and phage display selection. Crystallographic and mutagenesis studies of a dual specific Fab based on Herceptin revealed that distinct amino acids of this antibody engage energetically with its two antigens, HER2 and VEGF, although there is extensive overlap between the antibody surface areas contacting the two antigens. The high dual affinity is achieved and translated to dual action in vitro and in vivo.
Germaine Fuh, Ph.D., Scientist, Antibody and Protein Engineering, Research Division, Genentech, Inc.
We explored the ability of an antigen-binding site to interact with two unrelated protein antigens using an engineering approach and phage display selection. Crystallographic and mutagenesis studies of a dual specific Fab based on Herceptin revealed that distinct amino acids of this antibody engage energetically with its two antigens, HER2 and VEGF, although there is extensive overlap between the antibody surface areas contacting the two antigens. The high dual affinity is achieved and translated to dual action in vitro and in vivo.
Germaine Fuh, Ph.D., Scientist, Antibody and Protein Engineering, Research Division, Genentech, Inc.
11:30
Instant Immunity through Chemically Programmable Vaccination and Covalent Self-Assembly
The ability to instantly create a state of immunity as achieved in the passive transfer of hyperimmune globulin has had a tremendous impact on public health. Unlike passive immunization, active immunization, which is the foundation of vaccinology, is an anticipatory strategy with inherent limitations. Here we show that elements of active and passive immunization can be combined to create an effective chemistry-driven approach to vaccinology in cancer and infectious disease.
Carlos F. Barbas III, Ph.D., Kellogg Professor of Molecular Biology and Chemistry, The Scripps Research Institute
The ability to instantly create a state of immunity as achieved in the passive transfer of hyperimmune globulin has had a tremendous impact on public health. Unlike passive immunization, active immunization, which is the foundation of vaccinology, is an anticipatory strategy with inherent limitations. Here we show that elements of active and passive immunization can be combined to create an effective chemistry-driven approach to vaccinology in cancer and infectious disease.
Carlos F. Barbas III, Ph.D., Kellogg Professor of Molecular Biology and Chemistry, The Scripps Research Institute
12:00
Technology Workshops
IBC's Technology Workshops offer supplier and service companies the opportunity to present product and service offers directly to the audience at the conference. For more information on presenting a technology workshop at this meeting, please contact us. Three workshop slots are available in this time slot at the time of printing this brochure.
IBC's Technology Workshops offer supplier and service companies the opportunity to present product and service offers directly to the audience at the conference. For more information on presenting a technology workshop at this meeting, please contact us. Three workshop slots are available in this time slot at the time of printing this brochure.
12:30
Networking Luncheon, Last Chance for Exhibit and Poster Viewing
2:00
Announcements
Session VI: Expanding our Grasp and Use of Binding Sites in the Human Immune System
2:05
Chairperson's Opening Remarks
James S. Huston, Ph.D., Vice President & Senior Research Fellow, EMD Serono Research Center
James S. Huston, Ph.D., Vice President & Senior Research Fellow, EMD Serono Research Center
2:15
Pathogen Recognition by Toll-like Receptor 3 (TLR3)
The ectodomain (ECD) of TLR3 binds dsRNA, a molecular signature of viral pathogens, with high affinity. TLR3-ECD consists of a 23 turn solenoid bent into the shape of a horseshoe, each turn formed by one leucine-rich repeat motif. dsRNA binds at two widely spaced sites on one lateral face of the TLR3 horseshoe, and a third homotypic interaction brings two TLR3 molecules together at their C-terminal ends, triggering inflammatory responses.
David M. Segal, Ph.D., Chief, Immune Targeting Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health
The ectodomain (ECD) of TLR3 binds dsRNA, a molecular signature of viral pathogens, with high affinity. TLR3-ECD consists of a 23 turn solenoid bent into the shape of a horseshoe, each turn formed by one leucine-rich repeat motif. dsRNA binds at two widely spaced sites on one lateral face of the TLR3 horseshoe, and a third homotypic interaction brings two TLR3 molecules together at their C-terminal ends, triggering inflammatory responses.
David M. Segal, Ph.D., Chief, Immune Targeting Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health
2:45
Rational Development of High-Affinity T-cell Receptor-like Antibodies
T-cell receptor (TCR) avidity for a given pMHC is determined by number of MHC molecules, availability of co-receptors, and TCR affinity for MHC or peptide, respectively, with peptide recognition being the most important factor to confer target specificity. Here we present high-resolution crystal structures of 2 Fab antibodies in complex with the immunodominant NY-ESO-1(157-165) peptide analogue (SLLMWITQV) presented by HLA-A*0201 and compare them with a TCR recognizing the same pMHC.
E. Yvonne Jones, Ph.D., Principal Research Fellow, Division of Structural Biology, Oxford University, United Kingdom
T-cell receptor (TCR) avidity for a given pMHC is determined by number of MHC molecules, availability of co-receptors, and TCR affinity for MHC or peptide, respectively, with peptide recognition being the most important factor to confer target specificity. Here we present high-resolution crystal structures of 2 Fab antibodies in complex with the immunodominant NY-ESO-1(157-165) peptide analogue (SLLMWITQV) presented by HLA-A*0201 and compare them with a TCR recognizing the same pMHC.
E. Yvonne Jones, Ph.D., Principal Research Fellow, Division of Structural Biology, Oxford University, United Kingdom
3:15
Human Antibody Discovery and Optimization in Yeast
We have developed an integrated platform for the discovery and optimization of human IgGs in yeast. A synthetic library has been designed and constructed that reproduces key features of the preimmune human antibody repertoire. The abundance of nanomolar-affinity leads in this repertoire is 100-fold greater than that from published data for premier phage antibody libraries. Unprecedented speed from antigen to panels of human IgG protein is attained. Optimization of affinity and expression are robust and rapid within the platform.
K. Dane Wittrup, Ph.D., Office of the CSO, Adimab, Inc.
We have developed an integrated platform for the discovery and optimization of human IgGs in yeast. A synthetic library has been designed and constructed that reproduces key features of the preimmune human antibody repertoire. The abundance of nanomolar-affinity leads in this repertoire is 100-fold greater than that from published data for premier phage antibody libraries. Unprecedented speed from antigen to panels of human IgG protein is attained. Optimization of affinity and expression are robust and rapid within the platform.
K. Dane Wittrup, Ph.D., Office of the CSO, Adimab, Inc.
3:45
Networking Refreshment Break
4:15
Building Analogues of Antibody Binding Sites in Molecularly Imprinted Polymers
Applications of antibodies in therapy or diagnostics usually rely on an equilibrium binding between antibody and antigen after which ‘something else happens'. The ‘something else' event is often mediated by effector functions but may also involve simple clearance of the circulating complex. Molecularly imprinted polymers (MIPs) are analogs of antibodies for the first of these functions, the selective binding. Their application in analysis and extraction of toxic molecules, in proteomics analysis and to in vivo ‘clean up' will be discussed.
Anthony R. Rees, Ph.D., Chief Executive Officer, MIP Technologies AB, Sweden
Applications of antibodies in therapy or diagnostics usually rely on an equilibrium binding between antibody and antigen after which ‘something else happens'. The ‘something else' event is often mediated by effector functions but may also involve simple clearance of the circulating complex. Molecularly imprinted polymers (MIPs) are analogs of antibodies for the first of these functions, the selective binding. Their application in analysis and extraction of toxic molecules, in proteomics analysis and to in vivo ‘clean up' will be discussed.
Anthony R. Rees, Ph.D., Chief Executive Officer, MIP Technologies AB, Sweden
4:45
Engineered scFv Fusion Proteins for Targeted Delivery of RNA Therapeutic Agents - Small Interfering RNAs (siRNAs) are Attractive as Potential Therapeutic Agents
Transfected siRNA can "knock-down" certain mRNAs, but for therapeutic use in humans, available transfection methods are not sufficiently effective and safe. scFv-mediated import of siRNAs may present an alternative, and efficient import of intravenously injected CD4- and CCR5-specific siRNAs into transplanted human cells was achieved in a murine model of HIV infection, resulting in measurable control of viral infection. Attempts to eliminate leukemic cells via scFv-mediated import of siRNAs are underway.
Georg H. Fey, Ph.D., Professor of Genetics, University of Erlangen, Germany
Transfected siRNA can "knock-down" certain mRNAs, but for therapeutic use in humans, available transfection methods are not sufficiently effective and safe. scFv-mediated import of siRNAs may present an alternative, and efficient import of intravenously injected CD4- and CCR5-specific siRNAs into transplanted human cells was achieved in a murine model of HIV infection, resulting in measurable control of viral infection. Attempts to eliminate leukemic cells via scFv-mediated import of siRNAs are underway.
Georg H. Fey, Ph.D., Professor of Genetics, University of Erlangen, Germany
5:15
Antigen Binding Sites in the Fc region of IgG
f-star's Modular Antibody Technology can be used to engineer additional binding sites into antibody constant domains. We have developed yeast surface display libraries of IgG1 Fc randomized in non-CDR-loops (Fcabs). These libraries were used to select specific, low nM binders against a number of protein antigens. Fcabs are shown to induce ADCC with antigen-positive cells and show long half life. Fcabs have been used engineer multivalent or multispecific antibodies (mAb2) by replacing the Fc fragment with an Fcab.
Gottfried Himmler, Ph.D., Chief Scientific Officer, f-star Biotechnology, Austria
f-star's Modular Antibody Technology can be used to engineer additional binding sites into antibody constant domains. We have developed yeast surface display libraries of IgG1 Fc randomized in non-CDR-loops (Fcabs). These libraries were used to select specific, low nM binders against a number of protein antigens. Fcabs are shown to induce ADCC with antigen-positive cells and show long half life. Fcabs have been used engineer multivalent or multispecific antibodies (mAb2) by replacing the Fc fragment with an Fcab.
Gottfried Himmler, Ph.D., Chief Scientific Officer, f-star Biotechnology, Austria
5:45
Close of Session
Workshop: Sunday | Main Conference: Monday | Tuesday | Wednesday | Thursday
7:30
Networking Coffee
8:00
Announcements
Session VII: Exploring the Limits of Tumor Targeting with Molecular Formats
8:05
Chairperson's Opening Remarks
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
8:15
Tumor Targeting with Immunoliposomal Anticancer Drugs
Interest in the use of selectively targeted nanomedicines for the delivery of anticancer small molecule therapeutics, or gene medicines, is expanding rapidly. Recent research in the Allen lab explores the use of combination targeting strategies; these strategies are showing improved therapeutic outcomes in cancer. Examples include: increasing the 'apparent' receptor density on target cells by targeting to two or more surface receptor(s); targeting to two different cellular targets; and targeting combinations of therapeutic molecules with different modes of action.
Theresa M. Allen, Ph.D., Professor of Pharmacology & Oncology, University of Alberta; Strategic Advisor, Center for Drug Research & Development (CDRD), Canada
Interest in the use of selectively targeted nanomedicines for the delivery of anticancer small molecule therapeutics, or gene medicines, is expanding rapidly. Recent research in the Allen lab explores the use of combination targeting strategies; these strategies are showing improved therapeutic outcomes in cancer. Examples include: increasing the 'apparent' receptor density on target cells by targeting to two or more surface receptor(s); targeting to two different cellular targets; and targeting combinations of therapeutic molecules with different modes of action.
Theresa M. Allen, Ph.D., Professor of Pharmacology & Oncology, University of Alberta; Strategic Advisor, Center for Drug Research & Development (CDRD), Canada
8:45
Efficient Tumor Targeting with DARPins: Effects of Affinity, Format and Size
A systematic study with Designed Ankyrin Repeat Proteins (DARPins) specific for HER2 was carried out in targeting nude mice carrying xenograft tumors to establish the influence of size and affinity of protein-based targeting. Using DARPin point mutants ranging from pM to high nM with and without PEGylation, the optimal regimes for tumor targeting could be defined. With small high-affinity DARPins, a direct benefit of affinity is found, without any indication of a plateau or barrier effect, resulting in high levels and very large tumor to blood ratios, indicating their suitability for such therapeutic applications.
Andreas Plückthun, Ph.D., Professor of Biochemistry, Department of Biochemistry, University of Zürich, Switzerland
A systematic study with Designed Ankyrin Repeat Proteins (DARPins) specific for HER2 was carried out in targeting nude mice carrying xenograft tumors to establish the influence of size and affinity of protein-based targeting. Using DARPin point mutants ranging from pM to high nM with and without PEGylation, the optimal regimes for tumor targeting could be defined. With small high-affinity DARPins, a direct benefit of affinity is found, without any indication of a plateau or barrier effect, resulting in high levels and very large tumor to blood ratios, indicating their suitability for such therapeutic applications.
Andreas Plückthun, Ph.D., Professor of Biochemistry, Department of Biochemistry, University of Zürich, Switzerland
9:15
Tumor Targeting Theory - Kinetic & Diffusive Processes that Determine Antibody Macro & Microdistribution
A diverse array of tumor targeting agents ranging in size from peptides to nanoparticles is currently under development for applications in cancer imaging and therapy. However, it remains largely unclear how size differences among these molecules influence their targeting properties. Here we develop a simple, mechanistic model that can be used to understand and predict the complex interplay between molecular size, affinity, and tumor uptake.
K. Dane Wittrup, Ph.D., Dubbs Professor of Chemical Engineering & Biological Engineering, Massachusetts Institute of Technology
A diverse array of tumor targeting agents ranging in size from peptides to nanoparticles is currently under development for applications in cancer imaging and therapy. However, it remains largely unclear how size differences among these molecules influence their targeting properties. Here we develop a simple, mechanistic model that can be used to understand and predict the complex interplay between molecular size, affinity, and tumor uptake.
K. Dane Wittrup, Ph.D., Dubbs Professor of Chemical Engineering & Biological Engineering, Massachusetts Institute of Technology
9:45
Networking Refreshment Break
10:15
Tumor Microvasculature and Microenvironment: Novel Insight through Intravital Imaging
Intravital microscopy has provided unprecedented insights in tumor pathophysiology including angiogenesis and the microenvironment. Tumor vasculature has abnormal organization, structure, and function causing a hostile metabolic microenvironment characterized by hypoxia and acidosis and ineffective delivery and efficacy of therapeutics in tumors. In addition, host-tumor interactions regulate expression of pro- and anti-angiogenic factors, resulting in pathophysiological characteristics of the tumor. Restoration of imbalance of angiogenic factors in tumors normalizes tumor vasculature and microenvironment, and thus, improves concomitantly administered cytotoxic therapies.
Dai Fukumura, M.D., Ph.D., Associate Professor, Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School
Intravital microscopy has provided unprecedented insights in tumor pathophysiology including angiogenesis and the microenvironment. Tumor vasculature has abnormal organization, structure, and function causing a hostile metabolic microenvironment characterized by hypoxia and acidosis and ineffective delivery and efficacy of therapeutics in tumors. In addition, host-tumor interactions regulate expression of pro- and anti-angiogenic factors, resulting in pathophysiological characteristics of the tumor. Restoration of imbalance of angiogenic factors in tumors normalizes tumor vasculature and microenvironment, and thus, improves concomitantly administered cytotoxic therapies.
Dai Fukumura, M.D., Ph.D., Associate Professor, Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School
10:45
Designing Nanoparticle Agents for Tumor Targeting and Imaging
We have developed a new class of biocompatible and nontoxic nanoparticles for in vivo tumor targeting and detection based on self-assembled nanostructures and pegylated colloidal gold. These pegylated gold nanoparticles are considerably brighter than semiconductor quantum dots with light emission in the near-infrared window. When conjugated to tumor targeting ligands such as single chain variable fragment (ScFv) antibodies, the conjugated nanoparticles are able to target tumor biomarkers such as epidermal growth factor receptors (EGFR) on human cancer cells and in xenograft tumor models.
Shuming Nie, Ph.D., Wallace H. Coulter Distinguished Faculty Chair in Biomedical Engineering, Director of Emory-Georgia Tech Cancer Nanotechnology Center, Emory University and Georgia Institute of Technology
We have developed a new class of biocompatible and nontoxic nanoparticles for in vivo tumor targeting and detection based on self-assembled nanostructures and pegylated colloidal gold. These pegylated gold nanoparticles are considerably brighter than semiconductor quantum dots with light emission in the near-infrared window. When conjugated to tumor targeting ligands such as single chain variable fragment (ScFv) antibodies, the conjugated nanoparticles are able to target tumor biomarkers such as epidermal growth factor receptors (EGFR) on human cancer cells and in xenograft tumor models.
Shuming Nie, Ph.D., Wallace H. Coulter Distinguished Faculty Chair in Biomedical Engineering, Director of Emory-Georgia Tech Cancer Nanotechnology Center, Emory University and Georgia Institute of Technology
11:15
Immunotargeted Delivery Across the Vascular Endothelium In Vivo
Targeting disease biomarkers for imaging and pharmacodelivery is limited by in vivo barriers restricting access. Endothelia prevent tissue penetration of imaging agents, drugs, nanoparticles and gene vectors. By integrating tissue subfractionation, subtractive proteomics, bioinformatics, antibody generation, and imaging modalities, we identify and validate vascular biomarkers that enable tissue-specific targeting and transport across the endothelium. Rapid tissue penetration improves in vivo imaging and therapeutic efficacy.
Jan E. Schnitzer, M.D., Scientific Director, Professor of Cellular & Molecular Biology, Director of Vascular Biology & Angiogenesis Program, Sidney Kimmel Cancer Center
Targeting disease biomarkers for imaging and pharmacodelivery is limited by in vivo barriers restricting access. Endothelia prevent tissue penetration of imaging agents, drugs, nanoparticles and gene vectors. By integrating tissue subfractionation, subtractive proteomics, bioinformatics, antibody generation, and imaging modalities, we identify and validate vascular biomarkers that enable tissue-specific targeting and transport across the endothelium. Rapid tissue penetration improves in vivo imaging and therapeutic efficacy.
Jan E. Schnitzer, M.D., Scientific Director, Professor of Cellular & Molecular Biology, Director of Vascular Biology & Angiogenesis Program, Sidney Kimmel Cancer Center
11:45
Lunch on Your Own
1:15
Announcements
Session VIII: Engineering Antibodies to Improve Cancer Therapy
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
Novel Antibodies that Bind to a Conformational Epitope of EGFR
Therapies directed against EGFR have shown clinical benefit in colorectal, lung and head and neck cancers, although toxicity including skin rash can be dose limiting. Through crystal structure studies we have identified a unique epitope of EGFR that is not exposed in the inactive state, but is available for antibody binding in the activated form expressed on tumor cells. MAb 806 binds selectively to tumor expressed EGFR, but not normal tissues, and has potent anti-tumor activity. Preclinical studies and clinical trial data on mAb806 will be presented.
Andrew Scott, M.D., Director, Ludwig Institute for Cancer Research, Australia
Therapies directed against EGFR have shown clinical benefit in colorectal, lung and head and neck cancers, although toxicity including skin rash can be dose limiting. Through crystal structure studies we have identified a unique epitope of EGFR that is not exposed in the inactive state, but is available for antibody binding in the activated form expressed on tumor cells. MAb 806 binds selectively to tumor expressed EGFR, but not normal tissues, and has potent anti-tumor activity. Preclinical studies and clinical trial data on mAb806 will be presented.
Andrew Scott, M.D., Director, Ludwig Institute for Cancer Research, Australia
2:00
Clinical Development of Genetically Engineered anti-GD2 Monoclonal Antibodies for Neuroblastoma
The ch14.18 chimeric anti-GD2 mAb mediates ADCC against neuroblastoma, particularly when combined with GM-CSF or IL2. Preclinical data indicate better antitumor control when tumor burden is small. A recent Children's Oncology Group Phase III trial showed ch14.18 + GM-CSF + IL2 was effective for high-risk patients in remission. The hu14.18-IL2 fusion protein, (IL2 linked to this mAb), is more effective in tumor-bearing mice than the combination of mAb+IL2. This fusion protein has Phase II activity; further development is underway.
Paul M. Sondel, M.D., Ph.D., Walker Professor of Pediatrics and Human Oncology, Division Head, Pediatric Hematology and Oncology, University of Wisconsin
The ch14.18 chimeric anti-GD2 mAb mediates ADCC against neuroblastoma, particularly when combined with GM-CSF or IL2. Preclinical data indicate better antitumor control when tumor burden is small. A recent Children's Oncology Group Phase III trial showed ch14.18 + GM-CSF + IL2 was effective for high-risk patients in remission. The hu14.18-IL2 fusion protein, (IL2 linked to this mAb), is more effective in tumor-bearing mice than the combination of mAb+IL2. This fusion protein has Phase II activity; further development is underway.
Paul M. Sondel, M.D., Ph.D., Walker Professor of Pediatrics and Human Oncology, Division Head, Pediatric Hematology and Oncology, University of Wisconsin
2:30
Ofatumumab, a Novel Human CD20 Antibody Therapeutic for B-Lymphoid Malignancies
CD20 represents one of the best validated targets for immunotherapy of cancer. Ofatumumab is a fully human IgG1 antibody generated from Ig-transgenic mice that targets a distinct small loop epitope on the CD20 molecule. Ofatumumab exhibits a slow off-rate, potently triggers antibody dependent cellular cytotoxicity, and displays an exceptional efficacy in recruiting complement and inducing specific cell lysis. Novel insights into its mechanisms of action and recent data from clinical studies in front line and refractory B-CLL and NHL patients will be discussed.
Jan van de Winkel, Ph.D., President R&D and Chief Scientific Officer, Genmab, The Netherlands
CD20 represents one of the best validated targets for immunotherapy of cancer. Ofatumumab is a fully human IgG1 antibody generated from Ig-transgenic mice that targets a distinct small loop epitope on the CD20 molecule. Ofatumumab exhibits a slow off-rate, potently triggers antibody dependent cellular cytotoxicity, and displays an exceptional efficacy in recruiting complement and inducing specific cell lysis. Novel insights into its mechanisms of action and recent data from clinical studies in front line and refractory B-CLL and NHL patients will be discussed.
Jan van de Winkel, Ph.D., President R&D and Chief Scientific Officer, Genmab, The Netherlands
3:00
Networking Refreshment Break
3:15
Improved Recombinant Immunotoxins Targeted to CD22-Positive Malignancies
Recombinant immunotoxins, antibody-toxin chimeric proteins, targeted to CD22 have produced complete remissions in patients with Hairy Cell Leukemia (HCL) but are less active against other B-cell malignancies. By making a modification to the toxin we have produced an immunotoxin, termed HA22-LR, which is smaller and more resistant to lysosomal proteases. In preclinical testing, HA22-LR was more potent for freshly isolated B-CLL cells and at least 10-fold less toxic for mice than earlier immunotoxins.
David J. FitzGerald, Ph.D., Chief, Biotherapy Section, Laboratory of Molecular Biology, Center of Cancer Research, National Cancer Institute
Recombinant immunotoxins, antibody-toxin chimeric proteins, targeted to CD22 have produced complete remissions in patients with Hairy Cell Leukemia (HCL) but are less active against other B-cell malignancies. By making a modification to the toxin we have produced an immunotoxin, termed HA22-LR, which is smaller and more resistant to lysosomal proteases. In preclinical testing, HA22-LR was more potent for freshly isolated B-CLL cells and at least 10-fold less toxic for mice than earlier immunotoxins.
David J. FitzGerald, Ph.D., Chief, Biotherapy Section, Laboratory of Molecular Biology, Center of Cancer Research, National Cancer Institute
3:45
Targeting Exposed Phosphatidylserine on Cancer Blood Vessels and Viruses
Phosphatidylserine (PS) is confined to the internal leaflet of the plasma membrane in resting mammalian cells. It becomes exposed on tumor blood vessels and on virus-infected cells in response to cell activation and oxidizing stresses. We have developed therapeutic monoclonal antibodies that cause innate immune cells to target and destroy PS-expressing cancer blood vessels and virus-infected cells. Bavituximab, our leading therapeutic anti-PS antibody, is showing good efficacy in clinical trials.
Philip E. Thorpe, Ph.D., Professor of Pharmacology, Serena S. Simmons Distinguished Chair, University of Texas Southwestern Medical Center
Phosphatidylserine (PS) is confined to the internal leaflet of the plasma membrane in resting mammalian cells. It becomes exposed on tumor blood vessels and on virus-infected cells in response to cell activation and oxidizing stresses. We have developed therapeutic monoclonal antibodies that cause innate immune cells to target and destroy PS-expressing cancer blood vessels and virus-infected cells. Bavituximab, our leading therapeutic anti-PS antibody, is showing good efficacy in clinical trials.
Philip E. Thorpe, Ph.D., Professor of Pharmacology, Serena S. Simmons Distinguished Chair, University of Texas Southwestern Medical Center
4:15
Antitumor Antibodies and the Immune Response to Cancer
Monoclonal antibodies (mAbs) can impact tumor biology by altering the tumor cell or by altering the host response to the tumor. Murine models have established that antitumor antibody efficacy depends on Fc receptor engagement and in humans, clinical outcomes are improved in individual expressing Fc receptor allotypes with higher affinity to IgG. We will discuss the role of ADCC and dendritic cells in shaping the antitumor response to mAbs in murine systems and evidence supportive of a contribution of adaptive antitumor immunity to clinical outcome.
Raphael Clynes, M.D., Ph.D., Associate Professor of Medicine, Columbia University
Monoclonal antibodies (mAbs) can impact tumor biology by altering the tumor cell or by altering the host response to the tumor. Murine models have established that antitumor antibody efficacy depends on Fc receptor engagement and in humans, clinical outcomes are improved in individual expressing Fc receptor allotypes with higher affinity to IgG. We will discuss the role of ADCC and dendritic cells in shaping the antitumor response to mAbs in murine systems and evidence supportive of a contribution of adaptive antitumor immunity to clinical outcome.
Raphael Clynes, M.D., Ph.D., Associate Professor of Medicine, Columbia University
4:45
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