Cambridge Healthtech Institute’s 8th Annual

Antibodies Against Membrane Protein Targets - Part 2

Antigen Engineering, Antibody Discovery, and Research Challenges

September 17 - 18, 2020 ALL TIMES EDT

As the pharmaceutical and biotech industries increasingly shift attention to biologics, much more attention is being paid to the prospect of developing membrane-bound targets for biotherapeutics. 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. 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 biologic drugs for these target families to advance into the clinic and beyond.

Thursday, September 17

PLENARY KEYNOTE PROGRAM

12:20 pm

PLENARY KEYNOTE: Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics

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.

12:45 pm LIVE Q&A:

Plenary Keynote Discussion

Panel Moderator:
Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.
Panelist:
William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics
12:55 pm LIVE PANEL AND Q&A:

Plenary Keynote Discussion: De-Risking Early Drug Discovery

Panel Moderator:
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
Panelists:
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Stephen A. Hitchcock, PhD, Head, Research, Takeda Pharmaceuticals, Inc.
1:35 pm Lunch Break - View Our Virtual Exhibit Hall

ANTIGEN DESIGN & ENGINEERING

2:05 pm 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.

2:25 pm

COVID-19 Therapeutic Development with Synthetic Antibody Technology

Mart Ustav, Jr., PhD, Post-Doctoral Fellow, Sidhu Lab, University of Toronto, Canada

As COVID-19 forced to pivot research activities, we rapidly focused on developing antibodies as potential diagnostic tools and therapeutics against SARS CoV-2. We rapidly implemented our synthetic antibody discovery platform to develop highly potent virus neutralizing antibodies. We demonstrate capability of rapidly developing fully human antibodies using phage displayed synthetic antibody libraries that have excellent drug-like properties.

2:45 pm 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

Multipass membrane proteins (MPs) such as G-protein coupled receptors and ion channels represent an important family of protein targets for the development of monoclonal antibodies (mAbs) to fight a wide variety of diseases ranging from cancer to inflammation, but a great technical challenge exists in displaying these MP antigens at their physiologically relevant conformations to produce mAbs with target specificity. Lipid nanodiscs (LNDs), the discoidal lipid bilayers of nanometer sizes encased by two copies of membrane scafold proteins (MSPs), represent a potentially powerful membrane platform for the development of MP-targeting mAbs with high specificity, but their utility is limited by the instability of detergent-solubilized MPs prior to reconstitution into LNDs, the instability of LNDs themselves, and the undesirable immunogenicity against MSPs. We address these limitations by developing synthetic amphipathic polymers and block copolymer membranes that substitute MSPs and lipid bilayers, respectively.

3:05 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Kevin Heyries, PhD, Co-Founder & Head, Business Development, AbCellera
Panelists:
Hongjun Liang, Associate Professor, Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center
Janice Robertson, PhD, Assistant Professor, Biochemistry and Molecular Biophysics, Washington University in St. Louis
Mart Ustav, Jr., PhD, Post-Doctoral Fellow, Sidhu Lab, University of Toronto, Canada
3:25 pm Session Break
3:45 pm Happy Hour - View Our Virtual Exhibit Hall
4:15 pm Close of Day

Friday, September 18

ANTIBODY DISCOVERY

10:00 am

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.

10:20 am 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.

10:40 am Discovering Therapeutic Antibodies to Challenging Multipass Transmembrane Targets
Meredith Hazen, 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.

Kevin Heyries, Ph.D., Co-Founder and Head of Business Development, AbCellera

High-throughput single-cell screening is enabling the rapid generation of large, diverse antibody sequence data. By combining immune repertoire sequencing with functionally validated single-cell data, we further expand antibody diversity accessible for lead identification. CeliumTm, AbCellera's interactive software, interprets these complex datasets using dynamic visual networks to guide selection.

11:20 am

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.

11:40 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Joseph Rucker, PhD, Vice President, Research and Development, Integral Molecular, Inc.
Panelists:
Zachary Britton, PhD, Scientist I, Antibody Discovery & Protein Engineering, MedImmune
Abhishek Datta, PhD, Senior Director, Antibody Discovery & Engineering, Scholar Rock
Tadas Panavas, PhD, Senior Principal Scientist, Biotherapeutics Molecule Discovery, Boehringer Ingelheim
Kevin Heyries, Ph.D., Co-Founder and Head of Business Development, AbCellera
Larry Green, Ph.D., CEO, Ablexis, LLC
John "Lippy" Lippincott, Ph.D., Vice President, Research, AlivaMab Discovery Services, LLC

AlivaMab Discovery Services produces low picomolar, neutralizing, development-ready human antibodies against even toxic targets in exceptionally fast timelines. Combining Ablexis' AlivaMab Mouse with ADS' proprietary AMMPD immunizations and direct-to-function screening puts projects on the fastest, most de-risked path from discovery through development and to market.

Panel Moderator:
Larry Green, Ph.D., CEO, Ablexis, LLC
John "Lippy" Lippincott, PhD, Vice President, Research, AlivaMab Discovery Services, LLC
12:40 pm Session Break

ISSUES AND CHALLENGES

12:55 pm New Therapeutic Modalities in Immunotherapy
Paul D. Rennert, PhD, President & CSO, Aleta Biotherapeutics

Two cell therapy and T cell engager technologies are advancing for diverse cancer indications. We developed novel proteins designed to complement and extend the functionality of cell therapeutics called bridging proteins. These can be considered CAR-T cell engagers by MOA. We present examples of the creation and evaluation of these proteins, for delivery to the patient as a biologic for injection or for delivery within the CAR T cell itself.

1:15 pm How Uncertainty in Patentability Will Impact Modality Selection for Biotherapeutics
John M. Conley, PhD, William Rand Kenan Jr. Professor, Law, University of North Carolina

The law is in chaos with respect to the patentability of medical diagnostics and therapies, DNA, RNA, and proteins. The PTO and courts are acting inconsistently. Last year Congress seemed close to passing clarifying legislation, but that effort died. This presentation addresses such questions as: Are existing patents that seem to restrict research really valid? Are new therapies likely to be patentable? If not, can they attract necessary capital?

R&D TOOLS AND WORKFLOWS

1:35 pm Structure of CD20 in Complex with the Therapeutic Monoclonal Antibody Rituximab
Lionel Rougé, 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.

1:55 pm

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.

2:15 pm 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.

2:40 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
John M. Conley, PhD, William Rand Kenan Jr. Professor, Law, University of North Carolina
Panelists:
Paul D. Rennert, PhD, President & CSO, Aleta Biotherapeutics
Lionel Rougé, PhD, Principal Scientific Researcher, Structural Biology, Genentech Inc.
Anna Yarilina, MD, PhD, Senior Scientist, AbbVie Bioresearch Center
3:00 pm Close of Conference

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