The field of protein engineering is at an exciting point in its development, with new generations of therapeutic antibodies now reaching the market, great advances in protein science and a body of clinical evidence that can be used to inform the development of safe, highly effective therapies for unmet medical needs. At PEGS, Engineering Antibodies presents the state of the art in technologies used by protein engineers working at the discovery and design stage to quickly and efficiently craft biotherapeutics directed at the most elusive targets and biological functions. Emphasis will be given to new presentations that highlight unpublished work in this important field.
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WEDNESDAY, MAY 6
7:00 am Registration and Morning Coffee
8:00 Chairperson’s Remarks
Jonas V. Schaefer, Ph.D., Head, High-Throughput Laboratory, Department of Biochemistry, University of Zurich, Switzerland
8:10 KEYNOTE PRESENTATION
NGS and Computational Motif Analysis to Identify the Antibody Epitope Specificities that Co-Associate with a Disease Phenotype
Patrick Daugherty, Ph.D., Professor, Chemical Engineering, Biomolecular Science and Engineering, University of California, Santa Barbara
Autoimmune diseases frequently exhibit conserved antibody specificities in advance of clinical symptoms. The identification of the preferred and possibly environmental antigen targets of these antibodies has proven exceptionally challenging. Given this, we developed a method to characterize human antibody specificity repertoires in individual patients. Combining bacterial display peptide libraries with massively parallel sequencing and computational analysis we demonstrate the capability to discover disease associated antibodies and their environmental antigens.
8:40 A Monoclonal Antibody that Targets a NaV1.7 Channel Voltage Sensor for Pain and Itch Relief
Ru-Rong Ji, Ph.D., Professor, Anesthesiology and Neurobiology, Duke University Medical Center
Both loss-of-function and gain-of-function human mutations strongly suggest that the sodium channel subunit Nav1.7 is a key player in human pain sensation. However, a selective Nav1.7 blocker is lacking. I will present evidence showing a successful production of a Nav1.7 monoclonal antibody. This antibody not only blocks sodium currents in HEK cells, but also inhibits action potentials and synaptic transmission in native neurons and relives pain and itch in mice.
9:10 Rapid Development of Antibody Therapeutics for Infectious Disease Outbreaks
Wayne A. Marasco, M.D., Ph.D., Professor of Medicine, Harvard Medical School
Human mAbs may have a role in an outbreak setting for the prophylaxis and early treatment of emerging viral pathogens. However, obtaining timely access to B cells from infected patients for targeted selection is often challenging and can delay the discovery process. These restrictions have led us to use an ultra large non-immune human Ab-phage display library as a resource for the isolation of neutralizing mAbs to several emerging pathogens.
9:40 Antibody Therapeutics for CNS Diseases and Delivery across the Blood-Brain Barrier
George Thom, Senior Scientist, Antibody Discovery and Protein Engineering, Medimmune
The blood-brain barrier (BBB) protects and regulates the homeostasis of the brain. However, this barrier also limits the transport of systemically administered drugs, including large molecule therapeutics, to the brain. This results in sub-therapeutic concentrations of drug reaching CNS targets. Therefore, we have developed a BBB targeting system, using receptor-mediated transport, which can deliver human IgGs across the BBB and elicit a pharmacodynamics response.
10:10 Phage Display Derived Calcium-Dependent Biparatopic Antibody for Eliminating High Plasma Concentration Target Antigen
Shinya Ishii, Research Scientist, Research Division, Chugai Pharmaceutical Co., Ltd.
Enhancing soluble antigen clearance from plasma can be a novel approach to enhance the efficacy of antibody therapeutics. In our previous report, pH dependent antigen binding antibodies can reduce antigen concentration from plasma. Here we report a novel approach to further accelerate the antigen elimination from plasma. We will discuss multimeric antibody-antigen immune complex mediated approach using phage display derived calcium-dependent biparatopic antibody.
10:40 Coffee Break in the Exhibit Hall with Poster Viewing
11:25 Antibody Discovery Using Single-Cell Technologies
J. Christopher Love, Ph.D., Associate Professor, Chemical Engineering, Koch Institute, Massachusetts Institute of Technology
This talk will describe the use of microscale technologies to enable the identification of new antibodies from single B cells, and the recovery of the producing cells for single-cell sequencing. Applications of a platform based on arrays of nanowells to examine both specificity and function of antibodies, including neutralizing activity at the single-cell level, will be discussed. Integration of these data with next-generation sequencing will also be presented.
11:55 Multiplex Technologies to Improve Binder Generation and Characterization
Jonas V. Schaefer, Ph.D., Head, High-Throughput Binder Selection Laboratory, Biochemistry, University of Zurich
Screening thousands of affinity reagent candidates and analyzing their specificity remains one of the major bottlenecks in binder generation. In my presentation, I will highlight our recent developments using a mixture of adapted and novel technologies to improve these steps and thus to increase the speed and efficiency of our binder generation pipeline. In addition, innovative applications of our selected binders will be presented.
12:25 pm Use of Engineered CHO Cell Libraries for Improves
Pierre-Alain Girod, Ph.D., CSO, Selexis
12:55 Luncheon Presentation (Sponsorship Opportunity Available)
or Enjoy Lunch on Your Own
1:55 Session Break
2:10 Chairperson’s Remarks
George Thom, Ph.D., Senior Scientist, Antibody Discovery and Protein Engineering, Medimmune
2:15 A Pipeline for the Discovery of immunoPCR Reagents
Andrew Ellington, Ph.D., Research Professor of Biochemistry, University of Texas at Austin
While antibodies are remarkable reagents for diagnostics, they are surprisingly underutilized for an older but powerful technology, immunoPCR. We will lay out a pipeline for mining immune repertoires for antibodies, conversion of antibodies to single chain or other formats, attachment of single oligonucleotide tags, and use in immunoPCR. I will also address methods for the high-throughput development of antibody libraries with unique nucleic acid tags that may be suitable for NextGen immunoPCR methods.
2:45 Enhanced IgG Hexamerization Mediates Efficient C1q Docking and More Rapid and Substantial Complement-Dependent Cytotoxicity (CDC): Preclinical Proof of Concept
Janine Schuurman, Ph.D., Vice President, Research, Genmab
We revealed that IgG antibodies form hexamers on the cell surface following antigen binding. These hexamers are critical for optimal C1q binding and CDC. IgG hexamerization occurs through specific non-covalent interactions between Fc-segments. We now identified mutations that enhanced IgG clustering after antigen binding to cells which led to an increase in C1q binding and CDC. Our data represent a promising novel approach for improving the efficacy of therapeutic antibodies.
2:50 Structurally Motivated Approach To Design Bispecific Antibodies With Improved Developability Properties
Srinath Kasturirangan, Ph.D., Scientist I, Antibody Discovery and Protein Engineering, MedImmune
While current scFv-based BiSAbs offer a variety of geometries between antigen binding sites, some spacing options are lacking. Using a structurally-motivated approach we designed additional variants with scFvs inserted into surface-exposed loops of an IgG1 Fc. The scFvs in these BiSAb variants are N- and C-terminally constrained, potentially preventing domain exchange and aggregate formation, thereby precluding the need for scFv engineering to stabilize the molecule.
3:15 CO-PRESENTATION: Creating Focused Mutant Libraries for Protein Engineering
Alain Ajamian, Ph.D., Director, Chemical Computing Group
Michael Drummond, Ph.D., Applications Scientist, Chemical Computing Group
Protein engineering plays a pivotal role in modulating the function, activity and physical properties of biologics. However, the efficient engineering of protein sequences with desirable properties can be challenging given the excessively large sequence space. Here we have developed a computational approach which predicts mutation probabilities for given residue sites in specified sequences. In assessing the probabilities at given residue sites, the sequence search space can be efficiently sampled to design and produce focused mutant libraries.
3:45 Refreshment Break in the Exhibit Hall with Poster Viewing
4:45 Computational Design of Protein Antigens
William R. Schief, Ph.D., Professor, Immunology & Microbial Science, Scripps Research Institute; Director, Vaccine Design, International AIDS Vaccine Initiative
We have engaged in a variety of immunogen design projects aiming to induce antibodies against specific structural epitopes. These bring challenges such as stabilizing epitope conformation, influencing antibody angle of approach, enhancing affinity and specificity for particular germline precursors, presenting structural epitopes in a membrane context, and engineering glycoprotein epitopes. This talk will review a few case studies, highlighting lessons learned.
5:15 OptMAVEn: De Novo Design of Antibody Variable Regions
Costas D. Maranas, Ph.D., Professor, Chemical Engineering, Pennsylvania State University
OptMAVEn is a computational tool for the de novo design of the entire antibody variable region against a given antigen epitope. It simulates in silico the in vivo steps of antibody generation and evolution, and is capable of capturing key critical structural features responsible for affinity maturation of antibodies. A new humanization procedure was developed, tested, and incorporated into OptMAVEn. OptMAVEn was applied to design neutralizing antibodies targeting influenza hemagglutinin and HIV gp120.
5:45 Networking Reception in the Exhibit Hall with Poster Viewing
7:00 End of Day
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THURSDAY, MAY 7
8:00 am Morning Coffee
8:30 Chairperson’s Remarks
Janine Schuurman, Ph.D., Vice President, Research, Genmab, Denmark
8:35 Antibody Therapeutics: Charting a Course in Rough Seas of Intellectual Property
Konstantin M. Linnik, Ph.D., Partner, Intellectual Property, Nutter, McClennen & Fish, LLP
Antibody IP is crowded – the number of antibodies in development far exceeds the number of targets. The recent Federal Circuit case, Abbvie v. Centocor, related to anti-IL12, and the emerging battle in BMS v. Merck, related to anti-PD-1, are just two of several recent cases shaping up the future of antibody IP. How do these developments in patent law affect commercialization opportunities for antibody therapeutics?
9:05 NGS-Based Characterization of Antibody Responses Following Vaccination
Sai Reddy, Ph.D., Assistant Professor, Biosystems Science and Engineering, ETH Zurich
Next-generation sequencing (NGS) of antibody repertoires offers the promise to aid existing immunological technologies such as serum antibody titers, which capture the functional phenotype of an immune response but does not provide quantitative information on molecular diversity and distribution. We have developed a systems vaccinology framework, which will facilitate the characterization of vaccine formulations by novel means, enabling a more complete evaluation of alterations to the landscape of antibody responses.
9:35 Ligand Discovery for T Cell Receptors Using Yeast Display
Michael Birnbaum, Ph.D., Postdoctoral Fellow, Stanford University School of Medicine
A hallmark of T cell receptors and their MHC ligands is extreme diversity, which complicates their study. Recently, we have created a method to systematically determine the peptide-MHC binding specificities of immune receptors of interest. The method combines libraries of pMHC molecules displayed on yeast, binding-based receptor selections, deep sequencing, and computational predictions. Together, these methodologies allow highly accurate predictions of what peptide-MHCs will activate a given TCR.
10:05 Coffee Break in the Exhibit Hall with Poster Viewing
11:05 An Antibody Discovery Platform for Efficient Mining of the B Cell Repertoire
Daniel Lightwood, Ph.D., Director, Antibody Discovery, UCB-Celltech
UCB’s core antibody discovery technology enables extremely efficient interrogation of the natural antibody repertoire. The platform combines high-throughput B cell culture screening and a proprietary technique called the “fluorescent foci method” to identify and isolate single, antigen-specific, IgG-secreting B cells. The talk will provide case studies of the application of the platform to antibody discovery projects, including the use of bone marrow derived plasma cells as a source of mAbs.
11:35 Realizing the Therapeutic Potential of Antibodies Derived from a Human Immune Response – Case Studies in Indications of Oncology and Infectious Disease
Kristine M. Swiderek, Ph.D., Chief Scientific Officer, Theraclone Sciences
Theraclone discovers novel targets and antibodies and develops therapeutic monoclonal antibodies by using its proprietary B cell technology platform I-STAR to mine the immune system of patients who have mounted a disease impacting immune response. Our focus is to explore the memory B cell repertoire of cancer patients who demonstrate durable responses to immunotherapy including, e. g. checkpoint inhibitors, cancer vaccines and others. Case studies will be presented that illustrate this discovery approach.
12:05 pm Computational Approaches to Antibody Design: Improvements to the Predictions of Structure, Stability and Affinity
David A. Pearlman, Ph.D., Senior Principal Scientist, Schrödinger
We discuss computational advances demonstrating significant promise both for improved prediction of antibody structure from sequence, and for the ability to predict the changes in stability and affinity resulting from residue mutations. The Prime approach to de novo loop prediction is an appreciable improvement over previous methods for CDR loop prediction, while substantive improvements to free energy calculations (FEP) allow us to calculate stability and affinity changes with high precision.
12:35 End of Conference
5:15 Registration for Dinner Short Courses