Antibodies Against Membrane Protein Targets - Part 1

 

( 抗膜蛋白质标的的抗体 – 第一部分 )

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

9月16日(一)

1:00 pm Pre-Conference Short Course Registration
Click here for details on short courses offered.

9月17日(二)

7:00 am Registration Open and Morning Coffee

Innovation In Targeting Membrane Proteins

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.

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

Antigen Generation And Optimization

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

David Maurer, Principal 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

Strategies For Generating Antibodies Against Membrane Proteins

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, PhD, 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.

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. Visit the conference website for discussion topics and moderators.

6:05 Welcome Reception in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)

7:10 Close of Day

9月18日(三)

7:30 am Registration Open and Morning Coffee

Structural Biology

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 Presentation to be Announced

9:35 Coffee Break in the Exhibit Hall with Poster Viewing

Panel Discussion

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


PLENARY KEYNOTE PROGRAM
Click here for full abstracts.

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

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

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

* 活动内容有可能不事先告知作更动及调整。

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