Display of Antibodies

The evolution of phage and yeast display techniques have enabled a vast array of constructs that include bispecific antibodies, antibody-drug conjugates, immunotherapy constructs, T cell receptors, and membrane proteins with ever greater potency and target specificity. The 22nd Annual Display of Antibodies conference at the PEGS Summit convenes the premier leaders in antibody engineering every year to review the latest technology developments that are advancing the field of biologics forward. Don’t miss this significant milestone in the year to learn about new approaches to solving the challenges that remain in protein engineering and hear about the latest tools that are being deployed including structure-based drug design, deep sequencing and single cell analysis.

Monday, August 31

STATE-OF-THE-ART IN ANTIBODY ENGINEERING

9:00 am

Chairperson's Opening Remarks

K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
9:05 am KEYNOTE PRESENTATION:

Design of Bispecific Antibodies: From Heavy/Light Chain Pairing Preferences to Mitigating High Viscosity

Paul J. Carter, Genentech Fellow, Antibody Engineering, Genentech

Bispecific antibodies are of growing interest with two currently marketed and over 100 more in clinical development. This talk will offer some mechanistic understanding of antibody heavy/light chain pairing preference and application to the efficient production of bispecific IgG in single host cells. The second part of this talk will focus on elevated antibody viscosity at high concentration, which can be limiting for subcutaneous delivery, as well as manufacturing. Specifically, a novel mutational strategy was devised to mitigate high viscosity of monospecific and bispecific antibodies that may complement existing methods.

9:25 am

Addressing Antibody Developability by Mammalian Display

John D. McCafferty, PhD, CEO & Founder, IONTAS

As well as having appropriate binding affinity, it is important that clinical drug candidates are non-polyreactive and have optimal biophysical properties allowing formulation at high concentrations. Our mammalian display platform has allowed direct selection of antibody variants with reduced polyreactivity and aggregation propensity from large mammalian display libraries. Thus, mammalian display addresses developability issues during the earliest stages of lead discovery and significantly de-risks the future development of antibody drugs.

9:45 am

Selection and Optimization of Antibodies against Multipass Membrane Proteins in situ on Cell Surfaces

Robert Pejchal, PhD, Director, Antibody Engineering, Adimab LLC

Whole cell selections extend discovery of yeast-presented antibodies to integral membrane proteins, such as GPCRs. A case study from initial binder identification to functional characterization of affinity-optimized antagonist leads against a GPCR will be presented. Affinity optimization by selection and high-throughput selection-free screening of antibody variants will be discussed, along with takeaways for leveraging multiple cell lines in NGS-based enrichment analysis of highly diverse library selection outputs.

10:05 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
Panelists:
John D. McCafferty, PhD, CEO & Founder, IONTAS
Robert Pejchal, PhD, Director, Antibody Engineering, Adimab LLC
Paul J. Carter, Genentech Fellow, Antibody Engineering, Genentech
10:30 am Coffee Break - View our Virtual Exhibit Hall

STATE-OF-THE-ART IN ANTIBODY ENGINEERING (CONT.)

10:45 am

Chairperson's Remarks

K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
10:50 am

Next-Generation Platforms for Antibody Discovery

Andrew R.M. Bradbury, PhD, CSO, Specifica, Inc.

Antibody display libraries have served as a rich source of therapeutic antibodies. However, antibody leads selected from display libraries usually require downstream affinity and developability optimization, extending lead development timelines and costs. Specifica has established a unique antibody discovery display platform based on natural antibody sequences in which sub-nanomolar antibodies, requiring minimal optimization, are routinely selected.

11:10 am

Choosing the Right Platform: Applications of in vivo and in vitro Systems across the Discovery Pipeline

Melissa Geddie, PhD, Principal Scientist, Antibody Discovery, Biogen

Deciding which platforms to use for new campaigns is an important step in the antibody discovery process. Some considerations include the purpose of the antibodies (reagents vs. therapeutics), as well as the difficulty of the target. Recent campaigns at Biogen will be discussed that highlight the advantages and disadvantages of our in vivo and in vitro platforms.

Birgit Viira, PhD, Key Account and Technology Officer, Icosagen

We take advantage of our universal HybriFree antibody discovery engine to efficiently discover therapeutic antibody candidates by direct cloning from COVID-19-recovered patients’ blood samples. HybriFree method is further powered by our patented QMCF protein expression platform, permitting high-quality recombinant antigen and antibody production for pre-clinical research (including afucosylated antibodies for enhanced ADCC). Both technologies and relevant case studies will be presented, and discussed.

11:55 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
Panelists:
Melissa Geddie, PhD, Principal Scientist, Antibody Discovery, Biogen
Andrew R.M. Bradbury, PhD, CSO, Specifica, Inc.
Birgit Viira, PhD, Key Account and Technology Officer, Icosagen
12:15 pm Lunch Break - View our Virtual Exhibit Hall

NGS AND MACHINE LEARNING IN ANTIBODY DISCOVERY

1:05 pm

Semi-Supervised Machine Learning in the Identification of Antibody Leads from in vitro Selections

M. Frank Erasmus, PhD, Head, Bioinformatics, Specifica, Inc.

One important goal of therapeutic selection campaigns is to generate diverse antibody panels that comprehensively explore epitope space. While antibodies with very different sequences are expected to bind different epitopes, it is not clear what constitutes a “different antibody”. This seminar will describe a semi-supervised machine learning tool that utilizes low-to-moderate-trained screening data coupled to unsupervised learning built around high-throughput, next-generation sequence information to improve lead prediction accuracy.

Aaron Sato, PhD, CSO, Biopharma, Twist Bioscience

Utilizing its proprietary DNA technology to write synthetic libraries, Twist Biopharma provides end-to-end antibody discovery and optimization solutions for the biotechnology industry.  This solution includes (1) a panel of highly diverse synthetic naïve antibody phage display libraries, (2) several target class specific antibody phage display libraries against difficult-to-drug targets, (3) a Twist Antibody Optimization (TAO) platform for antibody affinity and developability optimization and (4) a high-throughput antibody expression service.

1:50 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Andrew R.M. Bradbury, PhD, CSO, Specifica, Inc.
Panelists:
M. Frank Erasmus, PhD, Head, Bioinformatics, Specifica, Inc.
Aaron Sato, PhD, CSO, Biopharma, Twist Bioscience
2:10 pm Refresh Break - View Our Virtual Exhibit Hall
2:30 pm Problem Solving Breakout Discussions - Part A

This session provides the opportunity to discuss a focused topic with peers from around the world in an open, collegial setting. Select from the list of topics available and join the moderated discussion to share ideas, gain insights, establish collaborations or commiserate about persistent challenges.

TABLE 1: Can Mammalian Display Compete with Yeast and Phage? Challenges and Benefits of Mammalian Selection Systems for Protein Engineering

Jennifer A. Maynard, PhD, Henry Beckman Professor, McKetta Department of Chemical Engineering, Cockrell School of Engineering, University of Texas Austin
  • What are the trade-offs among reported mammalian systems?
  • What proteins are right for mammalian display? (GPCR, transport proteins and intramembrane proteases)
  • How can we design selections based on protein activity?
  • How to introduce and maintain a library – retroviral elements, CRISPR or others?
  • Can we simultaneously engineer glycosylation and proteins for desired functions?
  • How can we maximize library size, ensure just one variant per cell and maximize the dynamic range to separate populations of interest?
    3:00 pm Refresh Break - View Our Virtual Exhibit Hall
    3:20 pm Problem Solving Breakout Discussions - Part B

    TABLE 2: Enabling Technologies to Enhance Selections Based on Immune Function

    Jamie B. Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University
    • Interfacing new flow cytometry tools with directed evolution to facilitate functional selections
    • Yeast biopanning techniques to improve recognition of active signaling proteins
    • Choosing readouts to couple with selection process
    • Designing selection strategies to evolve proteins that enact therapeutic mechanisms of interest
    3:50 pm Refresh Break - View our Virtual Exhibit Hall

    PLENARY KEYNOTE SESSION

    4:10 pm

    Chairperson's Remarks

    K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
    4:15 pm

    From Energy to Machine Learning

    George M. Church, PhD, Robert Winthrop Professor, Genetics, Harvard Medical School

    In 1974, I adapted energy optimization methods for use in models of nucleic acids, protein and their interactions, and then for use in crystallographic refinement. In the last days of the second millennium,
    David Baker's team won the Critical Assessment of Structure Prediction (CASP) by an unbelievable margin. Since then, our labs exchanged 3 Ph.D. students (Dantas, Raman, Lajoie), Wannier from Mayo's group, Stranges from Kuhlman, and Mandell from Kortemme. We engineered new sensor proteins for metabolic
    engineering, essential proteins with non-standard amino acids for biocontainment, and polymerase-pore fusions
    for nanopore sequencing. None of this prepared us for the revolution following Gleb Kuznetsov joining our lab in 2012, joined soon by Surge Biswas, Pierce Ogden, Ethan Alley, and Sam Sinai. Together we abruptly moved to "sequence-only", deep machine learning for protein design -- ranging from fluorescent proteins to AAV capsids to antibodies. When combined
    with libraries of millions of designed gene segments from chip-synthesis and rapid testing, each design cycle can take large leaps in sequence space and function space.

    4:40 pm

    The Case for Intelligent Design in Protein Engineering

    Jamie B. Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University

    Directed evolution is in its prime, and it is deepening our understanding of biological systems and empowering therapeutic design. Recent breakthroughs in structural biology, computational design, and high-dimensional data analytics afford us the unprecedented opportunity to apply molecular, structural, and computational principles to guide protein engineering, employing a so-called “intelligent design” approach. This talk will highlight how my lab harnesses this interfacial approach to overcome the deficiencies of natural proteins.

    5:15 pm LIVE Q&A:

    Session Wrap-Up

    Panel Moderator:
    K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
    Panelists:
    George M. Church, PhD, Robert Winthrop Professor, Genetics, Harvard Medical School
    Jamie B. Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University
    5:35 pm Happy Hour - View our Virtual Exhibit Hall
    6:10 pm Close of Day

    Tuesday, September 1

    PROTEIN STRUCTURE FOR ENGINEERING PROTEINS

    9:00 am

    Chairperson's Remarks

    Gregory A. Weiss, PhD, Professor, Chemistry, Pharmaceutical Sciences, Molecular Biology & Biochemistry, University of California, Irvine
    9:05 am

    Mammalian Display Platform for Facile, FACS-Based Engineering of Antibodies, T Cell Receptors, and Viral Glycoproteins

    Jennifer A. Maynard, PhD, Henry Beckman Professor, McKetta Department of Chemical Engineering, Cockrell School of Engineering, University of Texas Austin

    Engineering of antibodies and related receptors is most commonly performed using phage or yeast display, but mammalian cells are used for production. To streamline engineering of these and other complex proteins, we developed a mammalian screening platform which allows for variant selection in the manufacturing host with near-native glycosylation. We have used this to identify human T cell receptors with sub-nanomolar affinities and modulate Fc binding to Fc receptors. Efforts to select for SARS-CoV-2 spike variants with increased stability and modified glycosylation sites to focus the immune response will be reported.

    9:25 am

    MicroED: Conception, Practice, and Future Opportunities

    Emma R Danelius, Postdoctoral Researcher, Biological Chemistry & Physiology, Univ of California Los Angeles

    In 2013, we unveiled the cryoEM method, Microcrystal Electron Diffraction (MicroED). The CryoEM is used in diffraction mode for structural-using crystals that are a billion times smaller than what is used for X-ray crystallography. In this seminar, I will describe the basics of this method, from concept to data collection, analysis and structure determination, and illustrate how samples that were previously unattainable can now be studied by MicroED.

    Saurabh Joshi, Phd, Associate Research Director, Discovery Biology, Syngene International Ltd

    Syngene provides a one-stop solution for large molecule discovery and development using multiple modalities such as classical hybridoma, phage display, and yeast display. Yeast display combines the advantages of both hybridoma and phage methods viz. ease of identification of high affinity, manufacturability, and a higher number of sequences. Our novel methodologies to generate the desired immune response in animals and expertise in yeast display has yielded great success in antibody discovery/development for various disease condition.

    10:10 am LIVE Q&A:

    Session Wrap-Up

    Panel Moderator:
    Gregory A. Weiss, PhD, Professor, Chemistry, Pharmaceutical Sciences, Molecular Biology & Biochemistry, University of California, Irvine
    Panelists:
    Emma R Danelius, Postdoctoral Researcher, Biological Chemistry & Physiology, Univ of California Los Angeles
    Jennifer A. Maynard, PhD, Henry Beckman Professor, McKetta Department of Chemical Engineering, Cockrell School of Engineering, University of Texas Austin
    Saurabh Joshi, Phd, Associate Research Director, Discovery Biology, Syngene International Ltd
    10:30 am Coffee Break - View our Virtual Exhibit Hall

    NGS AND MACHINE LEARNING IN ANTIBODY DISCOVERY

    10:50 am

    Structure-Guided Design of Immunogens Based on Flavivirus Glycoprotein E Domain III (EDIII)

    Jonathan R. Lai, PhD, Professor, Biochemistry, Albert Einstein College of Medicine

    Dengue virus is a mosquito-transmitted flavivirus that causes an estimated 390 million human infections each year. There are four serotypes of Dengue (DENV1-4) that can co-circulate in hyperendemic regions. Primary infection by a single serotype results in febrile illness and subsequent durable immunity to that serotype. Secondary infections by heterotypic serotypes can lead to severe shock syndrome and death. Severe Dengue disease is caused in part by cross-reactive antibodies elicited during primary infection that can bind heterologous DENV serotypes but cannot neutralize them. Instead, these non-neutralizing antibodies facilitate entry and infection in Fcg receptor positive cells thus causing "antibody-dependent enhancement" (ADE) of infection. The recent global emergence of Zika virus (ZIKV), a flavivirus that shares structural features with DENV, and the potential for ADE between DENV and ZIKV, raises concerns for vaccine strategies containing most or all epitopes in the E glycoprotein. The flavivirus E glycoprotein domain III (EDIII) is an attractive template for subunit vaccine design because it is relatively small (~100 residues) and is the target of potently neutralizing and protective antibodies for both DENV and ZIKV. However, there are limitations to the use of DENV and ZIKV EDIIIs as vaccines. For DENV EDIII, immunodominant regions lie outside of critical neutralizing epitopes, such as the broadly-neutralizing A/G-strand. Immunization of mice with ZIKV EDIII results in antibody responses to the neutralizing lateral ridge (LR) epitope, but also to the non-neutralizing ABDE sheet and CC'-loop epitopes. We have utilized structure-based protein engineering and phage display to mask unproductive epitopes of flavivirus EDIIIs by mutation while maintaining neutralizing epitopes. We have engineered these “resurfaced” EDIIIs from both DENV and ZIKV. Furthermore, we have developed protein nanoparticles containing EDIIIs from DENV and ZIKV using Spycatcher/Spytag conjugation technology. We will describe these design strategies and their potential for development of novel subunit vaccines.

    11:10 am

    Combining Machine Learning and Antibody Discovery

    Simon Friedensohn, Researcher, Biosystems Science & Engineering, ETH Zurich

    Next-generation sequencing of antibody repertoires has become a promising and powerful tool in the drug discovery process. However, its practical applications are often limited since selecting potential leads from sequencing data is challenging. Common approaches focus on screening the most abundant variants in a dataset or closely related variants of already known, functional antibodies. Thus, in many cases only a small fraction of the actual data is utilized. Modern machine learning methods are uniquely suited to unlock the true potential of antibody repertoire sequencing as they can fully utilize these large datasets to discover novel, previously hidden features. Here, we present a deep learning model that can be used to extract antigen-specific sequence patterns, that act as highly accurate, immunological biomarkers. Besides its diagnostic value, we show how this model not only facilitates antibody discovery, but also generates a large amount of rationally designed, novel in silico variants which can be used to identify promising lead candidates at an early stage during drug discovery.

    11:30 am LIVE Q&A:

    Session Wrap-Up

    Panel Moderator:
    Andrew R.M. Bradbury, PhD, CSO, Specifica, Inc.
    Panelists:
    Jonathan R. Lai, PhD, Professor, Biochemistry, Albert Einstein College of Medicine
    Simon Friedensohn, Researcher, Biosystems Science & Engineering, ETH Zurich
    11:50 pm Lunch Break - View Our Virtual Exhibit Hall

    PHAGE AND YEAST DISPLAY FOR EMERGING AND CHALLENGING TARGETS

    12:55 pm

    Chairperson's Remarks

    Jennifer R. Cochran, PhD, Shriram Chair & Professor, Bioengineering & Chemical Engineering, Stanford University
    1:00 pm

    Attacking the Cancer Surfaceome with Recombinant Antibodies

    James A. Wells, PhD, Professor, Departments of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California, San Francisco

    The cell surface proteome (surfaceome) is the primary hub for cells to communicate with the outside world. Oncogenes are known to cause huge changes in cells and we hypothesize transformation will lead to changes in the cancer surfaceome. Our lab uses proteomic technologies, both mass spectroscopy-based and a new multiplexed antibody method to systematically understand how cancer cells remodel their membrane proteomes. We then generate recombinant antibodies to detect and then attack these cells by toxifying the antibodies or recruiting immune cells to kill. I will describe our current studies in this area of attacking cancer from the outside.

    1:20 pm

    Antibody Fragments as Tools to Investigate G Protein-Coupled Receptor Signaling

    Andrew C. Kruse, PhD, Associate Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

    G protein-coupled receptors (GPCRs) are critical regulators of most aspects of human physiology, including control of cardiovascular function and metabolic homeostasis. New methods for synthetic antibody fragment discovery allow targeting of GPCRs, offering new insights into receptor structure, function, and signaling. In particular, GPCR-targeted antibodies now enable structural studies of receptor activation mechanisms, revealing in atomic detail how agonists trigger conformational changes and thereby activate cellular signaling pathways.

    1:40 pm

    Leveraging Next-Generation Yeast Display Libraries for Systems Immunology

    Aaron M. Ring, MD, PhD, Assistant Professor, Immunobiology, Yale School of Medicine

    Yeast have a remarkable capacity to functionally display a large fraction of the human exoproteome on their surface, including cytokines, growth-factors, and immunoreceptors. Using curated, genetically barcoded yeast libraries of these proteins, we have developed high-throughput approaches for antibody discovery, detection of protein-protein interactions, and characterization of functional humoral responses in patient samples.

    2:00 pm LIVE Q&A:

    Session Wrap-Up

    Panel Moderator:
    Jennifer R. Cochran, PhD, Shriram Chair & Professor, Bioengineering & Chemical Engineering, Stanford University
    Panelists:
    James A. Wells, PhD, Professor, Departments of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California, San Francisco
    Aaron M. Ring, MD, PhD, Assistant Professor, Immunobiology, Yale School of Medicine
    Andrew C. Kruse, PhD, Associate Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
    2:25 pm Refresh Break - View our Virtual Exhibit Hall
    2:40 pm Close of Display of Antibodies





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