About This Conference:
As the pharmaceutical and biotech industries shift their attentions from small molecule therapeutics to biologics, an increased amount of attention is being paid to the prospect of membrane proteins as drug targets for antibodies and other protein scaffolds. For these large target classes, biologics offer improved selectivity, an alternative for targets with known function that have not been amenable to small molecules and the potential for using antibodies for the targeted delivery of therapeutics. However, for the field to advance, fundamental challenges of antigen quality, screening methodology, antibody 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-and alternate scaffold-based therapeutics directed against these target families to advance into the clinic and beyond.
The first meeting in the set, Membrane Protein Targets and Targeting, will discuss the fundamental challenges associated with targeting specific membrane protein families, and provide updates of the application of nanobodies and other small protein scaffolds to optimize binding.
Wednesday, October 8
7:00 am Registration and Morning Coffee
8:05 Chairperson’s Opening Remarks
Benjamin Doranz, Ph.D., President & CSO, Integral Molecular Inc.
8:15 FEATURED Presentation: Evolving Stable GPCRs for Drug Screening and Structural Analysis
Andreas Plückthun, Ph.D., Professor of Biochemistry, University of Zürich, Switzerland
GPCRs are validated drug targets for small molecules and antibodies alike, yet their low expression levels and poor biophysical properties have limited progress. We have developed several technologies to evolve functional receptors with greatly improved stability in detergents, based on a polymer encapsulation of a whole E. coli library (termed CHESS). This has allowed us to crystallize functional GPCRs from protein produced in E. coli and use such receptors for advanced drug screening.
9:00 Discovery and Optimization of Novel Anti-G-Protein Coupled Receptor Monoclonal Antibodies
Trevor Wilkinson, Ph.D., Associate Director, Protein Sciences, Antibody Discovery and Protein Engineering, MedImmune, United Kingdom
G-protein coupled receptors represent a challenging target class for the isolation and optimization of therapeutic biologics. We have used a combination of immunization and phage display to isolate antibodies that potently block the activity of the formyl peptide receptor (FPR). Using combinatorial mutagenesis approaches, significant improvements to both affinity and species cross-reactivity of the lead molecules are demonstrated resulting in antibodies that show significant potency in cellular disease assays.
9:30 Using Patient Derived Tumor Models to Predict Response and Impact on Cancer Stem Cells by Targeting NOTCH and WNT Signaling Pathways
Christopher Murriel, Ph.D., Senior Scientist, Cancer Biology, OncoMed Pharmaceuticals
We previously demonstrated that targeting NOTCH, using an anti-DLL4 antibody, and WNT, using FZD receptor (OMP-18R5) or WNT ligand binding antagonists (OMP-FZD8-Fc) in patient-derived xenograft models (PDX), inhibited tumor growth and decreased CSC frequency. Additionally, anti-DLL4 and anti-WNT therapy decreased the expression of many genes associated with NOTCH, WNT, EMT, multidrug resistance, and DNA repair, with increased expression of differentiation markers. Therefore, our findings provide a rationale to target cancer stem cells through interference with NOTCH and WNT signaling pathways.
10:00 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Targeting of Clinically-Important GPCRs with Fully Human Antibodies
Barbara Swanson, Ph.D., Director, Research, Sorrento Therapeutics, Inc.
We are developing antagonistic fully human antibodies derived from our proprietary G- MAB® library targeting GPCR chemokine receptors, including CCR2, CXCR3 and CXCR5. These antibodies possess excellent in vitro characteristics regarding cell binding and inhibition of calcium flux and chemotaxis. The antibodies have been evaluated in pilot in vivo models and IND-enabling activities have been initiated for development as future anti-cancer and/or anti-inflammatory therapeutics.
11:15 Generation and Characterization of Antibodies against the Small Extra Cellular Loops of Glucagon Receptor
Bas van der Woning, Ph.D., Senior Scientist, arGEN-X, Belgium
Glucagon receptor (GCGR) is a type B GPCR, characterized by a large N-terminal domain that covers the small extracellular loops (ECLs). Glucagon activates GCGR by binding to the N-terminal domain and a pocket formed by the ECLs. By DNA immunization of outbred llamas we generated monoclonal antibodies (mAbs) binding to the N-terminal domain or to the ECLs of GCGR. Using these antibodies we will able to study the involvement of the ECLs in glucagon mediated GCGR activation.
11:45 Discovery of GPCR Antibody Therapeutics: Modulation of Cannabinoid Receptor 1 (CB1) Signaling
Erik Karrer, Ph.D., CSO, RuiYi, Inc.
Clinical and experimental evidence supports involvement of Cannabinoid Receptor 1 (CB1) signaling in metabolic and fibrotic diseases. RuiYi’s iCAPS technology (intramembranous conformation antigen presenting system) was used to generate antibodies to CB1 that recognize native structural epitopes. Antibodies with a range of functional activities were identified, including antagonist (inverse agonist), agonist and neutral effects on CB1 receptor signaling. Detailed in vitro characterization of an inverse agonist antibody will be presented.
12:15 pm Developing Functional Monoclonal Antibodies for Beta-3 Adrenergic Receptor
Lisa Minor, Ph.D., Business Development Consultant, Multispan, Inc.
Although GPCRs represent 40% of medicinal small molecule therapeutics, there are no successful monoclonal antibody therapeutics. Using cell based functional assays to characterize antibody properties may help develop successful therapeutics. In this presentation, we detail the development of Beta-3 adrenergic receptor mAbs characterized using Multispan’s GPCR cell based assay platforms. Our preliminary data show that several mAb clones specifically bound to the receptor while increasing the receptor function by acting as agonists.
12:45 Session Break
1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:40 Session Break
1:50 Chairperson’s Opening Remarks
Chris Mathes, Ph.D., Chief Commercial Officer, ChanTest Corporation
2:00 Featured Presentation: Fab Assisted Single Particle Cryo-EM Studies of Integral Membrane Proteins
Yifan Cheng, Ph.D., Associate Professor, Department of Biochemistry and Biophysics, University of California San Francisco
We developed a novel approach of using Fab to assist single particle cryo-EM studies of small integral membrane proteins. Using this approach, we determined a 3D reconstruction of a bacterial ABC exporter at ~8A resolution.
2:30 Development of Pore-Blocking Antibodies Targeting Ion Channels
Sam Xu, Ph.D., Senior Lecturer, Center for Cardiovascular and Metabolic Research, Hull York Medical School, United Kingdom
Antibody targeting ion channel pore is a very useful tool for studying individual ion channel functionality. We have developed TRP cationic channel and sodium channel pore-blocking antibodies with a strategy named E3-targeting. This concept has been successfully extended to other ion channel families. The talk will give an overview of recent development in the field including pore-blocking antibody design, generation, functional characterization, application and therapeutic potential.
3:00 Development of an Electrophysiological Screening Tool to Identify Sub-Type Selective Nicotinic Receptor Compounds
Glenn Kirsch, Ph.D., Senior Director, Pharmacology and Program Management, ChanTest Corporation
Our objective was to develop a screening tool for rapid identification of compounds with sub type-selective nicotinic receptor modulation properties. We developed cell lines and automated patch clamp assays for screening and profiling in IonWorks Barracuda. We will present progress in development, optimization and assay validation of cell lines that stably express human neuronal nicotinic receptors, including α3β4, α7, α4β2, and α3β4α5 subtypes.
3:15 Novel Strategies for Developing Functional Transporter and Ion Channel Assays
Nathan Zahler, Ph.D., Senior Scientist, XRPro Corporation
A high-throughput method for ion transporter and ion channel investigations based on X-ray fluorescence (XRF). This broadly applicable technique measures ion uptake and efflux using populations of cells without requirement for fluorophores or radiolabels. Results are insensitive to chemical form, permitting use of complex cell media including serum and high DMSO concentrations. This complimentary capability is efficient and is compatible with current HTS workflows.
3:30 Refreshment Break in the Exhibit Hall with Poster Viewing
4:10 Discovery of MAbs against Difficult GPCRs, Ion Channels, and Transporters
Joseph Rucker, Ph.D., Vice President, Research & Development, Integral Molecular
To enable the isolation, characterization, and engineering of MAbs against challenging membrane protein targets, Integral Molecular has developed the MPS Discovery Engine™ platform, encompassing Lipoparticles for concentrating native membrane proteins and Shotgun Mutagenesis for membrane protein engineering and epitope mapping. Using the MPS platform, we have generated inhibitory MAbs against the ion channel P2X3 for treating neuropathic and inflammatory pain, and have ongoing discovery programs against additional GPCR, ion channel, and transporter targets.
4:40 Generation of Monoclonal Antibodies to Understand the Structure and Function of TRPV2 Ion Channel
Matthew Cohen, Graduate Student, Case Western Reserve University
TRPV2 is a Ca2+-permeable cation channel implicated in numerous physiological processes including neuronal cell development. In order to define the cellular function of TRPV2 in neurons, we generated monoclonal antibodies using full-length recombinant TRPV2 as an antigen. These antibodies are suitable for detection of endogenous TRPV2 by western blot, immunoprecipitation and immunocytochemistry. Employing full-length TRP channels as antigens may allow for production of antibodies against other TRP channels of uncertain function in the future.
5:10 Interactive Breakout Discussion Groups
This interactive session provides conference delegates and speakers an opportunity to choose a specific roundtable discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.
Strategies for Developing and Testing Bispecific Antibody Therapeutics
Christopher Murriel, Ph.D., Senior Scientist, Cancer Biology, OncoMed Pharmaceuticals
- Identifying the best target combinations
- ADCCs as bispecifics
- Enhancing the role of immunomodulatory agents
Discovery of Monoclonal Antibodies against Membrane Embedded Targets
Bas van der Woning, Ph.D., Senior Scientist, arGEN-X, Belgium
- What approaches do you use to identify antibodies against membrane protein targets: naïve library display (yeast, phage); active immunization plus selections hybridoma technology, phage display, B-cell sorting, next generation sequencing?
- Preferred target material e.g. cells, membranes, VLPs, proteoliposomes, nanodiscs or loops/peptides for immunization, selection and screening
- Conformation specific selection / selection for agonistic clones
- Rodent and primate cross-reactivity
6:10 Welcome Reception in the Exhibit Hall with Poster Viewing
7:15 Close of Day
Thursday, October 9
7:30 am Registration and Morning Coffee
8:00 Chairperson’s Opening Remarks
Mark Tornetta, Ph.D., Scientist, Molecular Discovery Technologies, Janssen Pharmaceuticals
8:10 New Tools for Modification of Antibodies and Antibody Fragments
Hidde Ploegh, Ph.D., Member, Whitehead Institute, Professor of Biology, Massachusetts Institute of Technology
The application of sortase-catalyzed transacylation reactions to full sized antibodies and antibody fragments is a convenient and versatile tool to prepare derivatives over a wide spectrum of modifications. Applications of this methodology will be discussed.
8:40 Aquaporins as Potential Drug Targets for Antibody Therapeutics
Alan S. Verkman, M.D., Ph.D., Professor of Medicine and Physiology, University of California, San Francisco
The aquaporins are membrane water channels expressed widely in epithelia, endothelia and other cell types. Animal data suggest that modulation of aquaporin function or expression could have therapeutic potential in edema, cancer, obesity, brain injury, glaucoma and other conditions. Autoantibodies against AQP4 cause the autoimmune demyelinating disease neuromyelitis optica, for which a monoclonal non-pathogenic anti-AQP4 antibody (aquaporumab) is in development.
9:10 Targeting Siglec-15 for Therapeutic Inhibition of Osteoclastic Bone Resorption Results in the Maintenance of Bone Formation
Mario Filion, Ph.D., CSO, Alethia Biotherapeutics
Siglec-15 has recently emerged as an osteoclast-specific receptor that could potentially be targeted therapeutically for treatment of bone loss. Antibodies targeting this receptor impair osteoclast differentiation and activity while maintaining bone formation by osteoblasts. The combination of antiresorptive activity with the maintenance of bone formation offers a new treatment paradigm in areas of unmet medical needs such as severe bone loss that occurs in multiple myeloma and invasive carcinomas.
9:40 Coffee Break in the Exhibit Hall with Poster Viewing
10:30 Solute Carriers as Targets for Biotherapeutics
Mathias Rask-Andersen, Ph.D., Post Doctoral Researcher, Department of Neuroscience, Functional Pharmacology, Uppsala University, Sweden
Solute carriers (SLCs) comprise a large family of membrane transporters. Despite being the largest family of membrane transport proteins, SLCs have been relatively under-utilized as therapeutic drug targets by approved drugs. To gain a better overview of the drug-targeted portion of the human proteome and the directions of current drug development, we developed a comprehensive dataset of established and clinical trial drug-target interactions.
11:00 Nanobodies® to Create Better Medicines: Clinical Validation with IL-6R and New Platform Opportunities
Antonin de Fougerolles, Ph.D., CSO, Ablynx, Belgium
Nanobodies are clinically validated small antibody fragments derived from heavy-chain only camelid antibodies. Data will be presented from the IL-6R Nanobody (ALX-0061) program that has demonstrated clinical efficacy in rheumatoid arthritis patients. In addition, unique aspects of the Nanobody platform will be exemplified using various pre-clinical and clinical stage programs.
11:30 Enjoy Lunch on Your Own
1:00 pm Plenary Keynote Program
Chas Bountra, Ph.D., Professor of Translational Medicine & Head, Structural Genomics Consortium, University of Oxford
Martin Tolar, M.D., Ph.D., Founder, President & CEO, Alzheon, Inc.
Andrew L. Hopkins, D.Phil, FRSC, FSB, Chair of Medicinal Informatics and SULSA Research Professor of Translational Biology, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee
2:45 Refreshment Break in the Exhibit Hall with Poster Viewing
3:45 Close of Conference