As the pharmaceutical and biotech industries increasingly shift attention to biologics, much more attention is being paid to the prospect of membrane-bound proteins as drug targets for antibodies and other protein scaffolds. For the large GPCR and ion
channel target classes, biologics offer improved selectivity, an alternative for targets with known function that have not been amenable to small molecule drugs and the potential for using antibodies for the targeted delivery of therapeutics. However,
for the field to advance, fundamental challenges in optimizing antigen quality and presentation, discovery methodologies, protein engineering and target identification must be resolved.
The two-part Antibodies Against Membrane Protein Targets 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- and
alternate-scaffold-based therapeutics directed against these target families to advance into the clinic and beyond.
The first meeting in the set surveys solutions to research and development challenges specific to the ion channel and GPCR target families, and offers presentations of biotherapeutics now advancing through development and clinical studies. The segment
also includes an in-depth session focusing on new ion channel and GPCR structures, new tools for structural biology and the key characterization assays used to understand binding and functional activity in these targets.
Final Agenda
Wednesday, September 26
7:00 am Registration Open and Morning Coffee (Foyer)
8:00 Welcome Remarks
Kent Simmons, Senior Conference Director, Cambridge Healthtech Institute
8:05 Chairperson’s Opening Remarks
Pravien Abeywickrema, Senior Scientist, Target Protein Design, Janssen Research & Development Inc.
8:10 Nanobodies to Ion Channel Targets; What Do We Know and Where Do We Want to Go?
Diane Van Hoorick, PhD, Senior Project Leader, Ablynx,
Belgium
Nanobodies, based on single-domain antibody fragments, retain target selectivity of full-length antibodies and in addition are easily engineered into multi-valents and multi-specifics. Based on these aspects, Nanobodies are ideal biologics for flexible
targets such as ion channels. Multiple functionally active Nanobodies modifying particular conformational and functional states in different channels were generated. Furthermore, multivalent engineering demonstrated that electrophysiological profiles
can be improved and combined into new modes of action.
8:40 Discovery of Functional Monoclonal Antibodies Targeting Ion Channels: Challenges and Solutions
Trevor Wilkinson, PhD, Associate Director, Antibody Discovery and Protein
Engineering, MedImmune Ltd., United Kingdom
Complex multi-spanning membrane proteins, such as GPCRs and ion channels, are attractive targets for therapeutics. Discovery of functional monoclonal antibodies targeting these proteins is challenging although advances in this area are being realized.
We will review the challenges in targeting ion channels with antibodies and provide an overview of the solutions being developed. We will illustrate progress in this field with case studies of ion channel antibody discovery.
9:10 KEYNOTE PRESENTATION: The High-Resolution Crystal Structure of the NavMs Sodium Channel Provides Information on Drug Binding
and Mutations Associated with Human Diseases
Bonnie Ann Wallace, PhD, Professor, Institute of Structural and Molecular Biology, Birkbeck College, United Kingdom
Our high resolution crystal structures of Nav mutations, along with molecular dynamics and spectroscopic, mutational and electrophysiology studies of the channel, have enabled visualization of the binding sites of channel-blocking drugs and the transmembrane
fenestrations that enable drug ingress into the channel, the changes in the voltage sensor and the channel gate associated with ion transport and the channel opening and closing, and the roles of mutations associated with human diseases.
9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)
10:25 Exploration of New Methods to Improve and Streamline Expression of Difficult to Express Membrane Proteins to Support Drug Discovery
Pravien Abeywickrema, Senior Scientist,
Target Protein Design, Janssen Research & Development Inc.
Integral membrane proteins represent more than 60% of current drug targets. Despite the clinical significance, therapeutic agents that target membrane proteins have been difficult to develop. Poor expression in recombinant systems is the most
critical challenge to producing functional membrane proteins for antibody discovery, structural and functional studies. The results from the exploration of different technologies for streamlined, efficient stable cell-line generation and transient
expression in mammalian cells for several GPCRs and ion channels will be presented.
10:55 A Multiplatform Strategy for the Discovery of Conventional Monoclonal Antibodies that Inhibit the Voltage-Gated Potassium Channel Kv1.3
Paul Colussi, PhD, Vice President, Research, TetraGenetics
We have isolated conventional antibodies that potently and selectively block the activity of Kv1.3, a voltage-gated potassium channel widely recognized as a therapeutic target for a variety of autoimmune diseases. We developed a general strategy
to achieve our goals by combining high-level expression of recombinant voltage-gated ion channels in Tetrahymena thermophila with immunization of phylogenetically diverse species and screening tools that allow deep-mining
of the immune repertoire.
11:25 Exploiting TRP Channels for Targeted Drug Entry
Bruce P. Bean, PhD, Professor, Neurobiology, Harvard Medical School
Many neurons mediating pain express TRPV1 or TRPA1 channels or both. The pores formed by these channels are unusual in allowing entry of very large cations, up to 450 Daltons. This property can be exploited to deliver cationic drug molecules
into the neurons. This mechanism can be used to produce long-lasting inhibition of pain, and can also be used to inhibit itch, cough, and inflammation involving release of inflammatory neuropeptides.
11:55 Efficient Membrane Protein Targeting Antibodies Discovery Using Synthetic Antibody Libraries and CIS Display
Guy Hermans, PhD, CSO, Isogenica Ltd.
12:25 pm Session Break
12:35 Luncheon Presentation: Discovery of Highly Specific Claudin 6 Antibodies for Targeting Cancer
Joseph Rucker, Vice President,
Research and Development, Integral Molecular
Oncology target Claudin 6 is upregulated in cancer and is not expressed in normal human tissue, unlike its closely related homolog Claudin 9. Integral Molecular has discovered specific Claudin 6 antibodies using its MPS Antibody Discovery
Engine. High-resolution epitope mapping, together with specificity analysis using the Membrane Proteome Array allowed selection of lead candidates mAbs. These mAbs bind unique residues on Claudin 6, creating novel intellectual property,
and lack reactivity for other cell surface proteins.
1:15 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)
1:50 Chairperson’s Remarks
Catherine Hutchings, PhD, Independent Consultant, United Kingdom
1:55 Pipeline Update on GPCR and Ion Channel Antibodies
Catherine Hutchings, PhD, Independent Consultant,
United Kingdom
G protein-coupled receptors (GPCRs) and ion channels represent some of the most important target classes for therapeutic drug discovery across a wide range of diseases. The progress made by antibody-based therapeutics directed to these target
classes will be reviewed outlining the breadth and diversity of antibody molecules, target opportunities in R&D and the clinical pipeline, including recent development to the expansion of opportunities afforded by next-generation modalities.
2:25 i-bodies against the Chemokine Receptor CXCR4 as a Treatment for Fibrosis
Mick Foley, PhD, CSO, AdAlta, Australia
i-bodies are small, stable, human scaffolds containing a long CDR3 that enable better access to proteins such as GPCRs and ion channels. We have obtained a panel of high affinity single domain antibodies specific for the chemokine receptor
CXCR4 which is a therapeutic target in fibrosis. The lead i-body AD-114 blocked SDF-1-induced leukocyte recruitment in an air pouch model of inflammation and the recruitment of fibrocytes into the lungs of mice with bleomycin induced
pulmonary fibrosis.
2:55 Overcoming Tolerance by Deep Mining of Natural Immune Repertoires
Kevin Heyries, PhD, Co-Founder, Business Development
and Strategy Lead, AbCellera
Antibodies from natural immune responses are widely regarded as superior to those generated by display technologies; however, immune tolerance poses a serious challenge for targets with high inter-species homology. Insoluble and poorly
immunogenic targets such as membrane proteins exacerbate this challenge. We show how AbCellera’s ultra-deep screening technology overcomes these challenges, producing hundreds of diverse rodent antibodies against targets
with 100% rodent-human homology, including G protein-coupled receptors.
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced (Grand Ballroom)
4:05 NEW: Targeting Membrane Proteins in their Native Context
Iwan Zimmermann, PhD, Postdoctoral Fellow,Institute of Medical Microbiology, University of Zurich, Switzerland
Antibody generation against native conformations of membrane proteins remains challenging and suffers from poor translation to binding in the native membrane context. We have established an in vitro selection procedure using three
differently shaped synthetic nanobody libraries called sybodies. This enabled us to rapidly generate conformation-selective high affinity binders against challenging membrane protein targets. Furthermore, we have developed NestLink,
a selection/screening hybrid technology centred on barcoding peptides that allows for deep mining of binder pools directly on cells.
4:35 Structural Insights into the Extracellular Recognition of the Human Serotonin 2B Receptor by an Antibody
Andrii Ishchenko, PhD, Senior Research
Associate, Structural Biology, USC
Given the importance of G protein-coupled receptors (GPCRs) as pharmaceutical targets, there has been an immense interest in therapeutic mAbs that act on GPCRs. We present the structure of a complex between the human 5-HT2B receptor
and a Fab fragment bound to the extracellular side of the receptor and highlight the structural determinants of Fab binding. The structure sheds light on the mechanism of selectivity in extracellular recognition of GPCRs by mAbs.
5:05 Interactive Breakout Discussion Groups
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.
Room: Back Bay B
Table 23: How Will We Accomplish Future Progress in Generating Therapeutic Biologics to Challenging Membrane Targets?
Moderator: Catherine Hutchings, PhD, Independent Consultant, United Kingdom
- GPCRs, ion channels, transporters, tetraspanins, etc.
- Target selection and validation of emerging targets
- Biology of disease, e.g., is there temporal and tissue ligand bias in disease?
- Biology of function, e.g., active, inactive or allosterism, antibody-based formats
- What has been an enablement (and what has been a distraction)?
Table 24: The Role of MS in Pharma: From Small to Large Molecules and Beyond
Moderator: Iain D. G. Campuzano, Principal Scientist, Discovery Attribute Sciences, Amgen
- Native-MS in pharma: Is it established or still niche?
- Required improvements for native-MS to become mainstream in pharma
- LC-MS and native-MS in membrane protein analysis: What role does it have?
- Specific MS improvements which would highly benefit pharmaceutical research
Table 25: Structure and Function of Membrane Proteins for Ab Production and Drug Development
Moderator: Bonnie Ann Wallace, PhD, Professor, Institute of Structural and Molecular Biology, Birkbeck College, United Kingdom
- Expression of membrane proteins (eukaryotic and prokaryotic)
- Structure and modelling of membrane proteins
- Antibody production against membrane proteins
- Drug binding (in vitro and in silico) to channels and receptors
6:05 Welcome Reception in the Exhibit Hall with Poster Viewing (Grand Ballroom)
7:10 Close of Day
Thursday, September 27
7:30 am Registration Open and Morning Coffee (Foyer)
8:00 Chairperson’s Remarks
Mariana Lemos-Duarte, PhD, Postdoctoral Researcher, Icahn School of Medicine at Mount Sinai
8:05 Confobody Enabled Structure Based Drug Discovery: Locking GPCRs in Functional Conformations
Sarah Triest, PhD, Scientist, Confo Therapeutics, Belgium
Camelid single domain antibodies are excellent tools to stabilize conformational states of GPCRs. Confo Therapeutics uses such conformation sensitive antibodies (Confobodies) to constrain GPCRs in the desired disease-linked
conformer as a starting point for drug discovery. The Confobody technology allows fragment screening of conformer-selective agonists with the desired efficacy profile and potency. A case study will be shown for the µ-opioid
receptor.
8:35 Novel Uses of FT-ICR for Membrane Protein, Nanodisc, mAb and ADC Analysis
Iain D. G. Campuzano, Principal
Scientist, Discovery Attribute Sciences, Amgen
Membrane proteins make up approximately 50% of possible “druggable” targets, making them very attractive molecules for many research groups. Native-MS analyses for accurate antibody, protein and nanodisc MW and
drug-to-antibody ratio (DAR) confirmation have traditionally been performed using oa-ToF instrumentation and more recently the extended mass range Orbitrap analyser with incremental improvements in data quality. Herein
we present the analysis of mAbs, ADCs, nanodiscs and PEGylated biotherapeutics using FT-ICR MS, with a specific focus for enabling membrane protein characterization.
9:05 Cancer and Immune Target Discovery with MabArray™
Shu-Hui Liu, PhD, Vice President, Therapeutics, Abmart
At Abmart we are employing our proprietary MabArrayTM platform to conduct tumor-centric, comprehensive discovery of cell surface targets and antibodies for oncology indication. These novel targets are currently being
developed into ADCs, CAR-Ts and other drug modalities for potential hematological and solid tumor indications.
9:35 Coffee Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)
10:20 Conformation-Specific Antibodies to Study GPCR Signaling
Mariana Lemos-Duarte,
PhD, Postdoctoral Researcher, Icahn School of Medicine at Mount Sinai
Activation of G-protein-coupled receptors such as opioid receptors lead to initiation of signaling cascades resulting in enhanced protein phosphorylation. Among the various kinases, protein kinase C is thought to play a crucial
role in the desensitization of opioid receptors. To explore this, I am using conformation-sensitive antibodies as unique tools to explore the role of protein kinase C in opioid receptor desensitization.
10:50 Characterization of Targeted Engineered Toxin Bodies (ETBs), Designed to Provide a Novel Mechanism of Action in Oncology
Erin Willert, PhD, Senior Vice President, R&D, Molecular Templates
Molecular Templates, a clinical stage biopharmaceutical company, develops highly potent, specific, next-generation immunotoxins. Engineered Toxin Bodies (ETBs) destroy cancer cells by enzymatic inactivation of ribosomes, a
mechanism of action distinct from other therapeutics, facilitating activity in the refractory/relapsed setting and in combination with other treatment modalities. Molecular Templates’ pipeline ETBs, proprietarily
de-immunized to avoid both innate and adaptive immune recognition, target cell surface receptors expressed on hematological and solid tumors.
11:20 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
11:50 Conference Registration Open (Foyer)
12:20 pm Plenary Keynote Program (Constitution Ballroom)
2:00 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)
2:45 Close of Conference