Cambridge Healthtech Institute’s 8th Annual

Antibodies Against Membrane Protein Targets - Part 1

Discovery and Development of Biologics Against GPCR, Ion Channel, and Transporter Targets

September 16 - 17, 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.

Wednesday, September 16

GPCR TARGETS

9:30 am Nanobodies Targeting and Modulating GPCR Function
Martine Smit, PhD, Professor, Target and Systems Biochemistry, Medicinal Chemistry, Vrije University, The Netherlands

G protein-coupled receptors (GPCRs) represent a major therapeutic target class as they play a key role in many (patho)physiological processes. Besides small molecules, GPCRs can be effectively targeted by biologics. In particular, antibody fragments from camelid-derived heavy chain-only antibodies (nanobodies/VHHs) are attractive tools in detecting, stabilizing, modulating and therapeutically targeting GPCRs. The small size and molecular structure of nanobodies allow extracellular and intracellular modulation of GPCR function. Besides modulating GPCR activity as monovalent or multivalent constructs, nanobodies can also be functionalized for imaging and therapy. Examples of nanobodies targeting human and viral chemokine receptors will be provided. Moreover, GPCR-binding nanobodies have been instrumental in obtaining crystal structures of GPCRs, facilitating structure-based drug discovery. Thus, nanobodies are an important class of biologics targeting GPCRs. 

9:50 am

GPCR-Targeted Antibodies in Hypertensive Diseases

Meredith A. Skiba, PhD, Postdoctoral Fellow, Biological Chemistry and Molecular Pharmacology, Harvard Medical School

Despite considerable interest in antibody-based therapeutics targeting GPCRs, few reported antibodies functionally modulate GPCR signaling. We developed a methodology to discover modulatory camelid antibody fragments (nanobodies) for GPCRs. Using this strategy, we identified nanobody antagonists for the angiotensin II type I receptor (AT1R), which regulates cardiovascular homeostasis. Our nanobody performs similarly to clinically used angiotensin receptor blockers (ARBs) and provides a strategy for targeting AT1R when ARBs are contraindicated.

10:10 am

Generation of Single Domain Antibody Antagonist and Agonist to Human Apelin Receptor

MeiYun Zhang, PhD, Principal Scientist, Antibody Discovery, Amgen Asia R&D Center

 

Developing functional antibodies targeting G-protein-coupled receptors remains challenging. Here we report structure-based and function-based approaches for generating functional single domain antibodies (sdAbs) against human apelin receptor (huAPJ). We co-crystallized an orthosteric sdAb antagonist complexed with huAPJ and converted it into an agonist by structure-guided design. We further developed an HTS method for directly isolating functional antibodies against GPCRs and identified a panel of sdAb antagonists and an agonist to huAPJ.


 

Nick Brown, North American Business Development Manager, Retrogenix Limited

Human cell microarray screening enables the discovery of specific primary cell surface receptors (i.e., druggable targets) as well as uncovering off-targets for a variety of biotherapeutic molecules, including peptides, antibodies and proteins, CAR T and other cell therapies. Case studies will focus on the assessment of off-target liabilities at an early stage and highlight the increasing role of the technology as an adjunct to, or replacement for, tissue cross reactivity studies prior to IND submissions.

10:50 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Meredith A. Skiba, PhD, Postdoctoral Fellow, Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Panelists:
Martine Smit, PhD, Professor, Target and Systems Biochemistry, Medicinal Chemistry, Vrije University, The Netherlands
MeiYun Zhang, PhD, Principal Scientist, Antibody Discovery, Amgen Asia R&D Center
Nick Brown, North American Business Development Manager, Retrogenix Limited
11:10 am Coffee Break - View Our Virtual Exhibit Hall
11:25 am Pipeline Update: 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 membrane protein drug target classes across a wide range of therapeutic areas. An update on antibody-based therapeutics in the GPCR/ion channel pipeline will be provided outlining the breadth and diversity of the target landscape, progress in preclinical and clinical development, including examples that highlight the successes and challenges faced with these target classes.

11:45 am Platforms for Production of Functional mAbs for Membrane Proteins
Eric Grazzini, PhD, Team Leader, Rapid Protein Production Life Sciences, National Research Council Canada

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

Shijie Wu, PhD, Application Scientist, Biosensing Instrument

G-protein coupled receptors play key roles in sensorial, metabolic, immunological and neurotransmission processes.  Despite its importance, quantifying the binding of drug candidates are difficult to do with traditional SPR techniques.  Results of kinetic measurements using SPR microscopy on GPCR and certain small molecules and antibodies will be shown in detail.

12:25 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Jean Labrecque, PhD, Section Leader, Translational Biosciences and Cellular Pharmacology, National Research Council Canada
Panelists:
Catherine Hutchings, PhD, Independent Consultant, United Kingdom
Shijie Wu, PhD, Application Scientist, Biosensing Instrument
12:45 pm Lunch Break - View Our Virtual Exhibit Hall

ION CHANNEL TARGETS

1:15 pm

Engineering of Tarantula Venom Peptides to Inhibit the Human Voltage-Gated Sodium Channel hNav1.7

Robert Neff, PhD, Principal Scientist, Neuroscience Drug Discovery, Janssen R&D, LLC

The voltage-gated sodium channel Nav1.7 is critical for amplifying pain signals. Selective blockers of Nav1.7 could provide analgesia with minimal side effects. One source of Nav1.7 drug discovery starting points are spider venoms that block voltage-gated sodium channels. This talk will discuss engineering efforts on huwentoxin-IV and protoxin-II, alterations in them that produced favorable changes in Nav1.7 potency and/or selectivity, and their ability to pharmacologically recapitulate the Nav1.7-null phenotype.

1:35 pm TRPA1 Agonists Reveal Ligand-Binding and Modality-Specific Pain Mechanisms
Jun Chen, PhD, MBA, Senior Scientist, Biochemical and Cellular Pharmacology, Genentech

We have identified various agonists of TRPA1 channel, and determined their ligand-binding and gating mechanism through biophysical and structural studies. Different from electrophilic agonists, non-covalent agonists activate TRPA1 without desensitization or tachyphylaxis, and evoke pain responses with different kinetics and sensitivity to antagonist treatment. Our study provides a pathway for the discovery of drugs tailored to specific disease conditions.

1:55 pm LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Jun Chen, PhD, MBA, Senior Scientist, Biochemical and Cellular Pharmacology, Genentech
Panelist:
Robert Neff, PhD, Principal Scientist, Neuroscience Drug Discovery, Janssen R&D, LLC
2:15 pm Session Break
2:35 pm Refresh Break - View Our Virtual Exhibit Hall
3:00 pm Interactive Breakout Discussions - View Our Virtual Exhibit Hall

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. Discussion topics and moderators will be listed on the website.

BREAKOUT: Characterization of Antibodies Against Membrane Proteins

Joseph Rucker, PhD, Vice President, Research and Development, Integral Molecular, Inc.
  • Affinity and Kinetics: Useful approaches for characterizing antibody binding​
  • Epitopes: Different techniques for epitope mapping; binning versus mapping; why do epitopes matter?
  • Specificity: Understanding off-target binding
  • Cell Function: Integrating functional assays into antibody discovery and development
3:35 pm Close of Day

Thursday, September 17

TRANSPORTER TARGETS

10:15 am

Isolation of State-Dependent Monoclonal Antibodies against the 12-Transmembrane Domain SLC2A4 Glucose Transporter

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

Transporter proteins control the movement of nutrients and other molecules across the cell membrane and are targets for diseases including diabetes and cancer. The structural complexity of transporters including SLC2A4 (GLUT4) pose a barrier in discovering MAbs for research and therapeutics. We leveraged our MPS Antibody Discovery platform to discover the first functional, conformation-dependent MAbs against SLC2A4. These MAbs selectively bind state-specific active forms of the transporter, providing new molecular tools for therapeutic discovery.

10:35 am

Role of Plasmodium Falciparum Chloroquine Resistance Transporter in Anti-Malarial Drug Resistance

Jonathan Kim, PhD, Postdoctoral Researcher, Physiology & Cellular Biophysics, Colombia University

Resistance to antimalarials such as chloroquine (CQ) and piperaquine (PPQ) has been associated with distinct sets of point mutations in the P. falciparum chloroquine resistance transporter PfCRT, a 49 kDa integral transmembrane protein localized in the digestive vacuole of the pathogenic parasite. We present the 3.2 Å structure of a PfCRT isoform from CQ-resistant, PPQ-sensitive South American 7G8 parasites, using a combination of single-particle cryo-electron microscopy and fragment antigen-binding technology.

SPECIAL PRESENTATION

10:55 am

Special Presentation: Emerging Technologies for Antigen Preparation and Stability

Keenan Taylor, PhD, Senior Scientist, AbbVie

The production of therapeutics targeting membrane proteins is frequently marred with challenges associated with the inherent properties of this class of proteins. Importantly, 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.

Aaron Sato, Chief Scientific Officer, Biopharma, Biopharma, Twist Bioscience

Twist Biopharma provides antibody discovery and optimization solutions.  To discover functional GPCR antibodies, we grafted GPCR-binding motifs into an antibody library.  Another approach mined the patented GPCR antibody sequences and used them to design another GPCR-focused library.  We can discover potent functional antibodies against GPCR targets using both libraries. 

11:35 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Joseph Rucker, PhD, Vice President, Research and Development, Integral Molecular, Inc.
Panelists:
Jonathan Kim, PhD, Postdoctoral Researcher, Physiology & Cellular Biophysics, Colombia University
Qiang Liu, Director, Antibody Engineering, Twist Bioscience
Keenan Taylor, PhD, Senior Scientist, AbbVie
11:55 am Coffee Break - View Our Virtual Exhibit Hall

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
2:05 pm 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






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