- 针对膜蛋白标靶的抗体 - Part 1 -


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

Ion Channel Targets

8:00 Welcome Remarks

Kent Simmons, Senior Conference Director, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Pravien Abeywickrema, Associate Principal Scientist, Target Protein Design, Merck & Co., 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

10:25 Exploration of New Methods to Improve and Streamline Expression of Difficult to Express Membrane Proteins to Support Drug Discovery

Pravien Abeywickrema, Associate Principal Scientist, Target Protein Design, Merck & Co., 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 New Understandings of the Therapeutic Targeting of TRP Channels

Jeffrey M. Herz, PhD, President and CEO, Algomedix, Inc.

Numerous members of the Transient Receptor Potential (TRP) superfamily of cation channels represent important targets for pharmaceutical drug development. Among this group, the thermo-TRPs, which include TRPV1, TRPM8, and TRPA1, have been the subject of both antibody directed and small molecule development efforts. This presentation will compare the strategies and progress in antibody-based therapeutics compared to small molecule antagonists for several important members of the TRP family.

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

Gpcr Targets

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 Presentation to be Announced

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:05 New Class of Precision Biologics that Target Specific GPCRs Conformations

Eric Grazzini, PhD, Team Leader, Rapid Protein Production, Human Health Therapeutics Portfolio, National Research Council Canada

The NRC aims to advance a functionally relevant conformational GPCR antigen presentation technology for high efficiency generation of mAbs for various therapeutic indications. Considering multiple GPCRs examples, we have demonstrated that most mAbs identified behave as PAM or NAM (positive or negative allosteric modulators), depending on the level of GPCR expression at plasma membrane. This presentation will demonstrate the value of our GPCR platform to identify lead candidates that target diverse intrinsic pharmacological properties selective toward active or inactive GPCR conformations.

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. Details on the topics and moderators are available on the conference website.

6:05 Welcome Reception in the Exhibit Hall

7:10 Close of Day

Thursday, September 27

7:30 am Registration Open and Morning Coffee

Characterization And Structural Biology

8:00 Chairperson’s Remarks

Sarah Sirin, PhD, Senior Scientist, AbbVie

8:05 Computational Modeling Applications in Development of Antibodies against Membrane Proteins

Sarah Sirin, PhD, Senior Scientist, AbbVie

Developing antibodies against membrane proteins is challenging, time consuming, and expensive. Computational methods that rely on sequence analysis and structure-based design can eliminate some of the guesswork and improve the likelihood of success for immunogen design. Here, we’ll describe some case studies where structure and computational modeling were integral to the design of immunogenic antigens and execution of successful antibody generation campaigns.

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 Sponsored Presentation (Opportunity Available)

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

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


12:20 pm Plenary Keynote Program

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing

2:45 Close of Conference

 

* 活动内容有可能不事先告知作更动及调整。

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