Membrane-bound proteins are attractive drug targets for antibodies and other protein scaffolds, but for the field to advance, fundamental challenges in optimizing antigen quality and presentation, discovery methodologies, protein engineering and target
identification must be resolved. This two-part meeting provides a forum in which discovery biologists and protein engineers can come together to discuss next-generation strategies and technologies that will allow antibody-based therapeutics directed
against GPCR and ion channel targets to advance into the clinic and beyond. Part 1, Antigen and Antibody Generation, will focus on best practices for antigen preparation, new approaches to antibody generation and the important
role of structural modeling and analysis – and track early stage, preclinical and clinical progress in this space.
Final Agenda
Monday, September 16
1:00 pm Pre-Conference Short Course Registration (America Foyer)
Click here for details on short courses offered.
Tuesday, September 17
7:00 am Registration Open and Morning Coffee (America Foyer)
8:00 Organizer's Welcome Remarks
8:05 Chairperson’s Opening Remarks
Catherine Hutchings, PhD, Independent Consultant, United Kingdom
8:10 Novel Biologies and Modalities for Targeting Membrane Proteins
Zhiqiang An, PhD, Professor, Chemistry; Director, Texas Therapeutics Institute, University of Texas Health Science Center at Houston
Rapid progress in the discovery of membrane proteins’ role in disease development provides a rich pool of targets for biologics-based drug modalities. Challenges in the development of these drugs include delivery across the BBB, targeting multiple
targets simultaneously, and specific delivery of cytotoxic drugs inside a cell and to the disease microenvironment. This presentation will provide an overview of opportunities and challenges in developing novel biologics targeting membrane proteins.
8:40 Clinical and Preclinical Progress in Targeting Membrane Proteins: What Is Working (and Not)?
Catherine Hutchings, PhD, Independent Consultant, United Kingdom
G protein-coupled receptors (GPCRs), ion channels and transporters represent some of the most important drug target classes across a wide range of diseases. An update on the clinical and preclinical progress made by antibody-based therapeutics directed
to these target classes will be presented along with examples of success and failure encountered in the R&D pipeline.
View Speaker Interview
9:10 KEYNOTE PRESENTATION: GPCRomics: “New” GPCRs That Expand Their Utility as Drug Targets
Paul A. Insel, MD, Distinguished
Professor, Pharmacology and Medicine, University of California, San Diego
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptor proteins and the most frequent targets (~35%) of approved drugs. However, only ~15% of the ~800 human GPCRs are currently targeted. This talk will discuss how GPCRomics
– approaches to identify and quantify endogenously expressed GPCRs in healthy and diseased cells and tissues – can reveal “new” GPCRs as targets for new therapeutics and the repurposing of approved drugs.
9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)
10:25 Functional Validation and High-Throughput Screening of Purified Ion Channel Proteins Using Reconstituted Proteoliposomes
Zhenwei Su, PhD, Senior
Scientist, Biomedicine Design, Pfizer, Inc.
Maintaining native confirmations and biological functions of purified membrane proteins greatly facilitates drug discovery. This presentation focuses on the use of reconstituted proteoliposomes as a powerful tool to validate functionality of purified
ion channel proteins. Validated proteins serve as valuable resources for immunizations and assay developments. The proteoliposome system also offers a screening method for the hit identification.
10:55 Large Asymmetric Nanodiscs and Their Applications in Drug Discovery
Mahmoud Nasr, PhD,
Instructor, Medicine, Brigham and Women’s Hospital
Lipids are asymmetrically distributed between the two leaflets of many biological membranes. Also, membrane proteins may assemble in functional clusters in the plane of the membrane. We have developed large nanodiscs up to 90 nm in diameter that are
suitable for reconstructing this asymmetry and can be used to study membrane protein complexes and virus entry. The methods for making these nanodiscs as well as their application in drug discovery will be presented.
11:25 Overcoming Production Challenges for Membrane Proteins in Antibody Discovery
Leyu Wang, PhD, Senior Scientist
and Project Leader, Protein Sciences, AbbVie
Antibodies against membrane proteins are highly attractive as therapeutics. The success to discover the therapeutic antibodies is critically depending on the quality of membrane protein itself. Due to the complex nature of membrane proteins, there
is no single method to address the membrane protein production challenges. Practical solution is to develop “fit-for-purpose” membrane production for immunization, display, screening and characterization that will be discussed in this
presentation.
11:55 Discovery and Development
of Antibodies Against Ion Channel Targets
Ted Clark, Founder & CSO, TetraGenetics, Inc.
Identifying antibodies that block ion channels is a challenging endeavor exacerbated by difficulties in producing recombinant protein in amounts that support drug discovery programs. We have developed a general strategy to address this challenge by
combining high-level expression of recombinant VGICs with immunization of diverse species and unique screening tools.
12:10 pm NGS-Guided Discovery of Fully-Human Antagonist Antibodies Against the Class A GPCR CXCR5
Valerie Chiou, Scientist, Distributed Bio
Due to their challenging structure within the membrane, generating functionally active antibodies against GPCRs remains an engineering challenge. We established a new cell-based panning method using our fully human computationally optimized phage
display library, establishing a general method for generating fully human and functional anti-GPCR therapeutic antibodies.
12:25 Session Break
12:35 Luncheon Presentation: Specificity Profiling and High-Resolution Epitope Mapping of Challenging MAbs
Benjamin
Doranz, PhD, MBA, President and CEO, Integral Molecular
Specificity testing across the proteome de-risks lead selection. We have tested hundreds of mAbs for specificity and off-target binding using our Membrane Proteome Array (MPA) platform. This platform contains 5,300 human membrane proteins, each expressed
in live cells in their native conformation. Conformational epitopes generate novel IP and mechanistic insights. We have mapped >1,000 such epitopes with a success rate >95% using our high-resolution Shotgun Mutagenesis Epitope Mapping platform.
1:15 Refreshment Break in the Exhibit Hall with Poster Viewing
1:50 Chairperson’s Remarks
Rajesh Vij, Senior Scientific Researcher, Antibody Engineering, Genentech
1:55 Antibody Discovery and Characterization in Absence of a Soluble Recombinant Target Antigen
Nikša
Kastrapeli, Director, Lead Identification, Biotherapeutics Molecule Discovery, Boehringer Ingelheim
Well-behaved, extensively characterized targets and their associated mechanisms are increasingly saturated with therapeutic options. The path to innovation often leads to exploring novel target antigens with difficult expression profiles and poorly
understood pathways. Therapeutic antibody generation relies on high-quality antigens that are functionally and structurally relevant to their natural forms. Here we will review options to generate and characterize antibodies without the luxury
of using a suitable soluble antigen protein.
2:25 New Tools to Characterize Antibodies against Membrane Proteins
Rajesh Vij, Senior
Scientific Researcher, Antibody Engineering, Genentech
Characterization of antibody-antigen interactions is an essential part of antibody development. This step becomes a larger bottleneck when targeting complex membrane proteins, due to limitations with existing assays. We will discuss a novel high-throughput
cell-based assay that can measure cell-based affinities and receptor expression levels and demonstrate how this workflow can support lead antibody selection.
2:55 High Quality Antibodies for Therapeutic Applications
Vera
Molkenthin, PhD, Chief Scientist, AbCheck
AbCheck discovers and optimizes human antibodies for therapeutic applications leveraging several proprietary platforms including in vitro and in vivo technologies. AbCheck delivers
high quality leads with subnanomolar affinities and good stabilities which are compatible with different antibody designs including bispecifics.
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
4:05 Single-Domain Antibody Fragments as Tools to Interrogate GPCR Structure and Function
Andrew C. Kruse,
PhD, Associate Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Camelid VHH antibody fragments have become versatile tools to study G protein-coupled receptor (GPCR) structure and signaling. Using a fully synthetic VHH fragment library displayed on yeast we developed high-affinity binders to the angiotensin
II type 1 receptor and used these to shed light on its activation mechanism and regulation by peptide agonists. These approaches are highly general to GPCR modulator discovery and provide a tool to accelerate GPCR research.
4:35 Modulating Effector Functions of Membrane Protein-Specific Heavy-Chain Antibodies through Hinge Engineering
Jamshid Tanha,
PhD, Research Officer, National Research Council, Canada
The effector functions of membrane protein-specific conventional and heavy-chain antibodies are known to be affected by Fc modification, i.e., glycan or protein engineering. Data on a series of hinge-engineered heavy-chain antibodies (HCAbs) are
presented and demonstrate that the effector functions of HCAbs can also be modulated simply by varying the length of the Ab hinge; this strategy may be useful to consider when engineering therapeutic heavy chain antibodies for optimal effector
functions.
Essex Ballroom
5:05 Interactive Breakout Discussion Groups - View All Breakouts
Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations
around a focused topic.
R&D for Emerging Modalities
Moderator: Zhiqiang An, PhD, Professor, Chemistry; Director, Texas Therapeutics Institute, University of Texas Health Science Center at Houston
- Consideration of alternative modalities for intended target
- Technologies for selections in final format
- Emerging technologies for antibody discovery; NGS, single cell analysis, CRISPR, AI
- Integrating traditional display platforms with new technologies
- Multispecific platforms
Fit-for-Purpose Membrane Protein Generation in Biologics Development
Moderator: Leyu Wang, PhD, Senior Scientist and Project Leader, Protein Sciences, AbbVie
- Best practices to decide approaches for membrane protein production
- Strategy for expression analysis for a novel multipanner
- Challenges to close gap between membrane protein supply and demand
- How to tap the external research organization or company
Structural Biology Challenges in R&D for Membrane Protein Targets
Moderator: Xinchao Yu, PhD, Senior Scientist, Cryo-EM, Amgen
- Producing sufficient quantity of minimally engineered human membrane proteins
- Crystallography vs. cryo-EM, pros and cons
- Detergents, nanodiscs or SMALPs
- High-throughput structural biology for membrane proteins
Additional Breakouts to be Announced
6:05 Welcome Reception in the Exhibit Hall with Poster Viewing (America Ballroom)
7:10 Close of Day
Wednesday, September 18
7:30 am Registration Open and Morning Coffee (America Foyer)
8:00 Chairperson’s Remarks
Friedrich Koch-Nolte, PhD, Professor, Laboratory of Molecular Immunology, University Medical Center Hamburg-Eppendorf, Germany
8:05 Applications of Cryo-EM for Discovery and Development of Antibodies against Membrane Protein Targets
Xinchao Yu, PhD, Senior Scientist, Cryo-EM, Amgen
Antibodies have shown great potential to facilitate cryo-EM structure determination of small membrane protein targets. Here we present the discovery and characterization of antibodies against an ABC transporter involved in cholesterol transport.
We solved the 3.3 Å resolution cryo-EM structure of the transporter with the help of 2 Fabs. The cryo-EM structure provides structural insight into substrate engagement to the transporter.
8:35 How Native-MS Can Complement X-Ray and CryoEM Studies in Understanding the Interactions of Membrane Proteins with Lipids and Proteins
Arthur Laganowsky, PhD, Assistant Professor, Chemistry, Texas A&M University
Native ion mobility mass spectrometry (IM-MS) is an emerging biophysical technique to probe membrane protein complexes and their interactions with lipids and other molecules. I will describe how native IM-MS can be used to determine thermodynamics
of individual ligand binding events to proteins. We also have developed native IM-MS approaches to unravel how individual lipid-binding events to membrane proteins can allosterically modulate their interactions with proteins and lipids.
9:05 Efficient Discovery of Single Domain Antibodies to Membrane Proteins Using a Synthetic Library
Guy Hermans, PhD, CSO, Isogenica Ltd
Isogenica’s llamdA™ library is a highly diverse, fully synthetic single domain VHH library. We will illustrate some of the unique benefits of VHH technology over conventional antibodies and demonstrate how the unbiased diversity
and lack of tolerance enables rapid and resource efficient isolation of VHH to membrane proteins. Examples will include the use of the library in ‘whole cell’ panning projects, as well as in selections using purified membrane
proteins complexes.
9:35 Coffee Break in the Exhibit Hall with Poster Viewing (America Ballroom)
10:20 Membrane Protein Tools and Technologies – What Is Working and What Isn’t?
Moderator:
Kevin Heyries, PhD, Co-Founder, AbCellera, Canada
Panelists: John Blankenship, PhD, Senior Investigator and Group Leader, Antibody Discovery, Novartis
Brian Booth, PhD, Senior Scientist, Drug Discovery, Visterra
Benjamin Doranz, PhD, MBA, President and CEO, Integral Molecular
Heike Wulff, PhD, Associate Professor, Pharmacology, School of Medicine, University of California, Davis
The challenging nature of membrane proteins has often dictated that researchers employ a toolbox approach to this work, cycling through a wide range of methods and technologies to find the best fit for a specific project. Join this panel –
shared between the Antibodies Against Membrane Targets and Antibody Forum audiences – for an interactive discussion of experiences with different discovery tools used in this space. You’ll hear perspectives from both panelists
and other audience members and have the opportunity to share your own questions and best practices.
11:20 Enjoy Lunch on Your Own
11:20 Conference Registration for Programs 1B-7B
12:20 pm Event Chairperson’s Opening Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute
12:30 Plenary Keynote Introduction
Anjan Chakrabarti, Vice President, Discovery Chemistry, Syngene International Ltd
12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells
David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University
1:20 PROTACs: Past, Present, and Future
Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University
2:00 Close of Plenary Keynote Program
2:00 Dessert Break in the Exhibit Hall with Poster Viewing (America Ballroom)
2:45 Close of Antibodies Against Membrane Protein Targets – Part 1 Conference
Please click here to continue to the agenda for Antibodies Against
Membrane Protein Targets – Part 2