Antibodies Against Membrane Protein Targets - Part 2


Cambridge Healthtech Institute 第5届
膜蛋白质标靶的抗体
第2部分:结构解析、表徵分析、生物医药品开发

第15届Discovery on Target其中一环

本会议由2部分所构成,新药发现相关生物学及蛋白质工程研究人员将齐聚一堂讨论次世代策略及技术,其实现了因应各种标靶家族的抗体和替代支架为基础的治疗药进入临床研究及其后阶段。

Final Agenda



Wednesday, September 27

11:50 am Conference Registration Open

12:20 pm Plenary Keynote Program

(click here for details)

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

Structural Biology

2:45 Welcome Remarks

Kent Simmons, Senior Conference Director, Cambridge Healthtech Institute

2:50 Chairperson's Opening Remarks

Ronnie Wei, Ph.D., Senior Principal Scientist, Sanofi-Genzyme

2:55 KEYNOTE PRESENTATION: State of the Science: Tools for Structural Studies of Membrane Protein Targets

Thomas P. Sakmar, M.D., Richard M. & Isabel P. Furlaud Professor, Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University; Guest Professor, Karolinska Institute, Sweden

Novel methods, including time-resolved X-ray crystallography and high-resolution molecular microscopy, often in combination with computational molecular dynamics simulations, are providing new insights about how membrane proteins really work. Developing biotherapeutics or small molecule drugs increasingly requires a multidisciplinary team effort to apply both new and traditional approaches to enhance pre-clinical drug discovery efforts. My goal is to provide an up-to-date critical summary of some new single-molecule drug discovery tools.

3:25 Large Scale Determination of Previously Unsolved Protein Structures Using Evolutionary Information from Metagenomic Sequence Data

Sergey_OvchinnikovSergey Ovchinnikov, Biologist, Baker Lab, Institute for Protein Design, University of Washington

Despite decades of work by structural biologists, there are still ~5200 protein families with unknown structure. We show that Rosetta structure prediction guided by residue-residue contacts inferred from evolutionary information can accurately model proteins that belong to large families and that metagenome sequence data more than triple the number of protein families with sufficient sequences for accurate modeling. We generate models for 614 protein families, of which 206 are membrane proteins.

3:55 Computational Advances in Antibody Discovery: Toward Earlier Assessment, Triage, and Optimization

David Pearlman, Ph.D., Director, Biologics Software Platform and Senior Scientist, Schrodinger

In the field of antibody drug discovery, there is growing realization that methods to assess, triage, and avoid liabilities in potential candidates must come early in the discovery process. Recent advances in computational approaches for antibody structure prediction, identification of protein liabilities (such as aggregation propensity), and in methods for protein engineering hold substantial promise in moving us closer to reaching this goal in an effective and efficient manner.

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

5:00 Structure and Function of Chemokine Receptors

Martin_GustavssonMartin Gustavsson, Ph.D., Post-Doctoral Scholar, Handel Lab, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego

Chemokines are small, secreted proteins that interact with G protein coupled chemokine receptors in the cell membrane to drive cell migration and regulate a number of physiological processes. I will present our recent advances in understanding the structure, dynamics and function of chemokine receptors using x-ray crystallography in combination with other biophysical and biochemical methods.

5:30 Entering GPCR Drug Discovery Space through Cryo-EM

Georgios_SkiniotisGeorgios Skiniotis, Ph.D., Professor, Molecular and Cellular Physiology and of Structural Biology, Stanford University Medical School

Recent technological breakthroughs have elevated cryo-EM to a principal choice of method for characterizing the structure of large macromolecular assemblies. GPCRs and their complexes have been challenging targets for cryo-EM, both because of their relative instability and small size, which limits accurate alignments for high-resolution 3D reconstructions. Nevertheless, atomic resolution cryo-EM of GPCRs is now within reach, opening up unprecedented opportunities for structure determination and drug discovery efforts in the field.

6:00 Implementation and Application of Internal Cryo-EM Lab for Support of Membrane Protein Research

Claudio_CiferriClaudio Ciferri, Ph.D., Senior Scientist, Structural Biology, Genentech

Recent breakthroughs in cryo-EM enabled atomic resolution structure determinations of several proteins including integral membrane proteins. At Genentech, we are establishing a state-of-the-art cryo-EM group to support small and large molecule drug discovery as well as basic research projects, with a particular focus on membrane proteins. In my talk, I will present the workflow we established to enable structure determination of our membrane protein targets in lipid bi-layer environment.

6:30 Close of Day

6:30 Dinner Short Course Registration

Click here for details on short courses offered. 

Thursday, September 28

7:30 am Registration Open

8:00 Interactive Breakout Discussion Groups with Continental Breakfast

Grab a cup of coffee and 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.

Characterization

9:00 Chairperson's Remarks

Joseph Rucker, Ph.D., Vice President, Research and Development, Integral Molecular, Inc.

9:05 Biophysical Characterization of Conformational States Accompanying GPCR Activation

Scott R. Prosser, Ph.D., Professor, Chemistry and Biochemistry, University of Toronto, Canada

The spectroscopic characterization of GPCRs reveals a complex conformational landscape, which responds to ligands, allosteric agents, and environmental factors. This ensemble description allows us to consider mechanistic concepts in light of well-known pharmacological phenomena including basal activation, inverse agonism, efficacy, biased signaling, and pre-coupling. Recent studies of the adenosine A2A receptor, a prototypical class A GPCR, will be presented and discussed in terms of consequences to drug discovery in GPCRs.

9:35 Mass Spectrometric Analysis of Membrane Proteins and Complexes in Biopharma

Iain Campuzano, Ph.D., Senior Scientist, Amgen

Membrane proteins make up approximately 50% of possible "druggable" targets, making them very attractive molecules for many research groups. Herein we will demonstrate how native mass spectrometric techniques are currently being used to determine membrane protein molecular weight and subunit stoichiometry. We will also demonstrate how the phospholipid number can be accurately derived for empty nanodisc particles. Finally, a UPLC-MS based method for accurate molecular weight determination will also be discussed.

10:05 Biophysical and Functional Characterization of GPCR Antagonistic Antibodies Raised in Chicken

Jennifer_KoenitzerJennifer Konitzer, Ph.D., Research Investigator, Immuno-Oncology Large Molecule Discovery, Bristol-Myers Squibb

Antagonizing the glucose-dependent insulinotropic polypeptide receptor GPCR (GIPR) may open up new therapeutic modalities in the treatment of diabetes and obesity. The receptor is highly conserved between rodents and humans, which has contributed to previous rodent immunization campaigns generating very few usable antibodies. Switching the immunization host to chicken enabled the generation of a large and diverse panel of monoclonal antibodies containing 172 unique sequences.

10:35 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

11:20 Structure-Based Protein Engineering to Improve the Characteristics of a Broadly Neutralizing Anti-HIV Antibody

Ronnie_WeiRonnie Wei, Ph.D., Senior Principal Scientist, Sanofi-Genzyme

Broadly neutralizing anti-HIV antibodies could be used to prevent or treat HIV infection. However, stability issues limit the therapeutic potential of some of these antibodies. A structure based protein engineering approach was deployed to identify the problematic residues and mutations were designed and screened for improved biophysical properties while maintain the breath and potency of one of these antibodies.

11:50 Joining Forces: Epitope Mapping and Structural Characterization of a Bispecific Antibody

Linda Kaldenberg-Hendriks, Scientist, Merus, The Netherlands

MCLA-128 is a human bispecific IgG targeting HER2 and HER3 that potently inhibits HRG-driven proliferation of HER2-amplified cancer cells. We have performed epitope mapping studies and generated high-resolution crystal structures for both arms of this bispecific antibody and their targets, as well as solution-state small-angle X-ray scattering data for the MCLA-128:HER2:HER3 complex. The resulting data were used to create a model for the unique mode of action of MCLA-128.

12:20 pm Sponsored Presentation (Opportunity Available)

12:50 Session Break

1:00 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:50 Refreshment Break in the Exhibit Hall with Poster Viewing

CASE STUDIES OF BIOTHERAPEUTIC DEVELOPMENT

2:35 Chairperson's Remarks

Catherine Hutchings, Ph.D., Independent Consultant, United Kingdom

2:40 Erenumab, an Anti-CGRP Receptor Antibody for Migraine Prevention

Cen_XuCen Xu, Ph.D., Scientific Director, Neuroscience Drug Discovery, Amgen

Generation of antagonist antibodies against the heterodimeric GPCR CGRP receptor is challenging due to the complex structure of the target. Erenumab (AMG 334) was created using a novel antigen that was designed based on the knowledge of how CGRP interacts with its receptor. This highly potent and selective antagonist antibody has now demonstrated efficacy in clinical studies for the prevention of episodic and chronic migraine.

3:10 Progress on the Development of Antibody Therapeutics against GPCR Targets

Catherine_HutchingsCatherine Hutchings, Ph.D., Independent Consultant, United Kingdom

G protein-coupled receptors (GPCRs) represent one of the most important target classes for therapeutic drug discovery across a wide range of diseases. The progress made by targeting GPCRs with antibody-based therapeutics will be reviewed outlining the breadth and diversity of antibody molecules and target opportunities in R&D and the clinical pipeline, including recent development to the expansion of opportunities afforded by next-generation modalities.

3:40 Session Break

3:55 Engineered Peptides Targeting Ion Channels in Pain and Immunology

Ron_SwansonRonald Swanson, Ph.D., Senior Director, Janssen

Animal venoms are a rich source of pharmacologically active peptides including ion channel blockers. However, properties such as the affinity, specificity, extended half-life, and manufacturability often must be engineered into the molecules. We have engineered scorpion peptides active against Kv1.3 to address the role of this channel in models of immune disease as well as spider toxin peptides active against Nav1.7, a target of high interest for pain.

4:25 Structure-Based Strategy to Develop Therapeutic Antibodies against Nav 1.7 for Pain

Luke_RobinsonLuke Robinson, Ph.D., Principal Scientist, Research, Visterra, Inc.

Ion channels remain a challenging class of targets to generate functional antibodies. Using our HeirotopeTM platform, an atomic network-based approach, we have incorporated a structure-guided approach to the discovery of antibodies targeting Nav1.7. We have engineered proteins to represent conformational and functionally relevant target epitopes of this channel. Application of these engineered proteins coupled with high-gain experimental methods, including droplet microfluidics, toward the discovery of therapeutic antibodies will be discussed.

4:55 Close of Conference

Please click here to visit the agenda for Antibodies Against Membrane Protein Targets Part One

* 活动内容有可能不事先告知作更动及调整。

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