Thursday, September 17
11:20 am Conference Registration for Part B Programs
12:20 pm Event Chairperson's Opening Remarks
An-Dinh Nguyen, Team Lead, Discovery on Target 2020, Cambridge Healthtech Institute
12:30 Plenary Keynote Introduction (Sponsorship Opportunity Available)
Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein
William G. Kaelin, Jr., MD, Professor and Investigator, Howard Hughes Medical Institute, Oncology, Dana-Farber Cancer Institute
VHL tumor suppressor protein (pVHL) inactivation is common in kidney cancer and upregulates the HIF2 transcription factor. PT2977/MK-6482 is an allosteric HIF2 inhibitor now in Phase 3 testing. Thalidomide-like drugs (IMiDs) bind to cereblon which, like pVHL, is the substrate-binding unit of a ubiquitin ligase. IMiDs redirect cereblon to destroy the myeloma oncoproteins, IKZF1 and IKZF3. We have developed new assays for identifying drugs that can destabilize oncoproteins of interest.
1:20 KEYNOTE PANEL DISCUSSION:
De-Risking Early Drug Discovery
Nadeem Sarwar, PhD, Founder & President, Eisai Center for Genetics Guided Dementia Discovery, Eisai, Inc.
- Data Sciences
- Novel Chemical Modalities
- Investment and Partnering Models
- COVID-19 Progress as Examples of Successful Partnerships
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Andrew Plump, MD, PhD, President, Research & Development, Takeda Pharmaceuticals, Inc.
2:00 Close of Plenary Keynote Program
2:00 Dessert Break in the Exhibit Hall with Poster Viewing
2:45 Organizer's Welcome Remarks
Cambridge Healthtech Institute
2:50 Chairperson's Remarks
Kevin Heyries, PhD, Co-Founder, Head of Business Development, AbCellera
2:55 Measuring and Modulating Equilibrium Assemblies of Oligomeric Membrane Proteins in Lipid Bilayers
Janice Robertson, PhD, Assistant Professor, Biochemistry and Molecular Biophysics, Washington University in St. Louis
How do greasy membrane proteins form stable complexes amidst the greasy lipid solvent of the cell membrane? Furthermore, how do changes in lipid composition affect the free energy of these assemblies? To investigate these questions, we have developed single-molecule microscopy methods for measuring the equilibrium free energies of membrane protein complexes in lipid bilayers and use these approaches to identify the thermodynamic driving forces underlying protein assembly in membranes.
3:25 Membrane Proteins without Membranes: Designed Resurfacing for Improved Solubility
Jeffery G. Saven, PhD, Professor, Chemistry, University of Pennsylvania
Computational methods can be employed to redesign natural proteins. Computational design of membrane proteins yields variants that retain wild-type structure and functionally related properties. The redesigned, water-soluble proteins fold in the absence of membranes and surfactants. We discuss the application of this approach to G-protein coupled receptors and ion channels.
4:25 Refreshment Break in the Exhibit Hall with Poster Viewing
5:00 Emerging Technologies for Antigen Preparation and Stability
Osvaldo Cruz-Rodriguez, PhD, Senior Scientist, Biologics Protein Purification, AbbVie Bioresearch Center
The production of therapeutics targeting membrane proteins is frequently marred with challenges associated with the inherent properties of this class of proteins. Over the years, many strategies have emerged to aid both in the production and stabilization of membrane proteins. Among these, the use of nanodisc technology and virus-like particles in both structural and clinical studies have become an increasingly popular alternative. Using an integral membrane protein antigenic target, we present a generalized workflow that incorporates both methodologies to generate purified protein in its native environment.
5:30 Engineered Virus-Like Particles for Developing Antibodies against Integral Membrane Proteins
Mart Ustav, Jr., PhD, Post-Doctoral Fellow, Sidhu Lab, University of Toronto, Canada
We have established a virus-like particle (VLP)-based antigen display system, that enables to specifically enrich integral membrane proteins based on an engineered interaction between the target membrane protein and the viral core protein. Linked with our high-throughput synthetic antibody discovery platform, we are effectively able to obtain highly functional antibodies against challenging membrane proteins.
6:00 Synthetic Membranes and Membrane Platforms that Mimic Lipid Bilayers to Support Membrane Proteins
Hongjun Liang, Associate Professor, Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center
Lipid nanodiscs (LNDs) support membrane proteins (MPs) with well-defined proteomembrane structures and accessible hydrophilic domains on both sides, but the utility of LNDs is limited by the instability of detergent-solubilized MPs prior to nanodisc reconstitution, the instability of LNDs themselves, and the interference between MPs and membrane scaffold proteins (MSPs). We address these limitations by developing synthetic amphipathic polymers and block copolymer membranes that substitute MSPs and lipid bilayers, respectively.
6:30 Dinner Short Course Registration (Premium Package or separate registration required)
7:00 Dinner Short Courses 10-12 (see Short Courses page for details)
9:30 Close of Day
Friday, September 18
7:00 am Registration
7:30 Interactive Breakfast Breakout Discussion Groups
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. Visit the conference website for discussion topics and moderators.
8:30 Transition to Sessions
8:40 Chairperson's Remarks
Joseph Rucker, PhD, Vice President, Research and Development, Integral Molecular, Inc.
8:45 Discovering Therapeutic Antibodies to Challenging Multipass Transmembrane Targets
Meredith Hazen, PhD, Senior Scientific Researcher, Genentech
Multipass transmembrane proteins are difficult targets for antibody generation due to the challenge of making a protein with native conformation. I will present a discovery strategy that resulted in the identification of antibodies that bind to extracellular epitopes of multipass transmembrane proteins. This strategy replaces the conventional hybridoma platform with a primary B-cell platform that mines more of the B-cell repertoire, resulting in a broad panel of diverse antibodies.
Structure- and Sequence-Based Design of Synthetic Single-Domain Antibody Libraries
Alex M. Sevy, PhD, Associate Scientist, Merck & Co.
We developed a synthetic VHH library for in vitro selection of single domain binders. We combine structure-based design and NGS analysis to build a library with characteristics that closely mimic the natural repertoire. Our platform confers several advantages over existing methods, such as using a humanized framework with nearly germline CDR1 and CDR2 sequences, this will serve as a useful tool for isolation of VHH as reagents and biotherapeutics.
9:45 Structural Design of Engineered Protein Constructs to Enable Antibody Discovery
Abhishek Datta, PhD, Senior Director, Antibody Discovery & Engineering, Scholar Rock
Scholar Rock’s insights into growth factor activation has led to the development of a platform to discover new medicines designed to selectively regulate growth factor activity in the local microenvironment of tissues. In this presentation, we will discuss how structural insights have enabled design of engineered proteins antigens that have led to discovery of antibodies with high specificity and unique mechanism of action against the TGFß family proteins.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
10:55 Strategies to Focus Phage Display Output on Specific Target Epitopes
Tadas Panavas, PhD, Senior Principal Scientist, Biotherapeutics Molecule Discovery, Boehringer Ingelheim
Often in antibody discovery the goal is to find binders that target a specific epitope on an antigen. In a standard phage display technique, a specific epitope for each binder is not defined until later in the process when scFvs or FABs from phage display are reformatted into IgGs. In this presentation we will showcase techniques that help to enrich phage display hits towards specific target epitopes.
Factors Governing the Success of Cell-Based Phage Selections
Zachary Britton, PhD, Scientist I, Antibody Discovery & Protein Engineering, MedImmune
Phage selections on whole cells ensures relevant presentation of membrane proteins in their native context. However, selections may be complicated by low target density, high background of irrelevant antigens, and structural features that limit accessibility of binding phage. A case study presents cell-based phage selections of two membrane proteins, which resulted in a highly successful antibody discovery effort and one that did not. Factors influencing discovery will be discussed.
12:25 pm Session Break
1:05 Refreshment Break in the Exhibit Hall with Poster Viewing
1:50 Chairperson's Remarks
Noel T. Pauli, PhD, Senior Scientist, Antibody Discovery, Adimab LLC
1:55 Structure of CD20 in Complex with the Therapeutic Monoclonal Antibody Rituximab
Lionel Rouge, PhD, Principal Scientific Researcher, Structural Biology, Genentech, Inc.
CD20 is a B cell marker of unknown function targeted by monoclonal antibodies (such as Rituximab) for the treatment of B cell disorders. We obtained a structure of CD20 in complex with Rituximab, revealing CD20 as a dimer bound by two Fabs; each Fab engages a composite epitope and an homotypic Fab:Fab interface. Our data suggest that Rituximab crosslinks CD20 into circular assemblies, leading to a model for complement recruitment.
Efficient Discovery of Antibodies against GPCRs by Combining Single B Cell Cloning with a Yeast-Based Expression Platform
Noel T. Pauli, PhD, Senior Scientist, Antibody Discovery, Adimab LLC
Integral membrane proteins represent a major class of therapeutic targets currently underserved by antibody-based drugs. Using a combination of immunization, single B cell isolation, and yeast-based cloning and expression, we have developed a high-throughput method to discover antigen-specific antibodies to a variety of membrane protein target classes. Here, we demonstrate the efficient and large-scale isolation of high-affinity antibodies against membrane protein targets, including CCR8, a class-A GPCR.
Next-Generation Strategies for Antibody Discovery to Membrane Proteins
Andrew Wollacott, PhD, Associate Director, Research, Visterra, Inc.
Hybridoma technology is a robust method for discovery of antibodies against challenging targets, despite advances in other antibody discovery platforms. We detail a case study for the discovery and optimization of anti-GPCR antibodies by integrating hybridoma technology with automation, next-generation DNA sequencing, and bioinformatic tools. The workflow circumvented the need for purified antigen and identified hundreds of functional antibodies and with high affinity and diverse modes of engagement.
3:25 Screening Strategies for Discovery of Functional Biologics
Anna Yarilina, MD, PhD, Senior Scientist, AbbVie Bioresearch Center
Successful biologic discovery requires development of comprehensive screening funnel. Introduction of functional assays early in the screening process enables effective selection of biologics with a desired mode of action and improves understanding of drug biology. This presentation will highlight benefits of the early implementation of functional assays into biologics screening funnel.
3:55 Close of Conference