Original Agenda
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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

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.

Tuesday, September 15

1:00 pm Pre-Conference Short Course Registration (Premium Package or separate registration required)
2:00 Short Courses 1-9 (see Short Courses page for details)
5:00 Close of Day

Wednesday, September 16

7:00 am Registration and Morning Coffee


8:00 Organizer's Welcome Remarks

Cambridge Healthtech Institute

8:05 Chairperson's Remarks

Catherine Hutchings, PhD, Independent Consultant, United Kingdom

8:10 Platforms for Production of Functional mAbs for Membrane Proteins
Eric Grazzini, PhD, Team Leader, Rapid Protein Production Life Sciences, National Research Council Canada

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.


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 antibody agonists targeting G-protein-coupled receptors (GPCRs) remains a big challenge. Here we report the co-crystal structure of human apelin receptor (APJ) with a potent orthosteric single-domain antibody antagonist, JN241, and the structure-guided conversion of JN241 into a full agonist, JN241-9, to human APJ. Modeling and molecular dynamics simulation shed light on JN241-9-stimulated receptor activation, providing structural insights for discovering agonistic antibodies against class A GPCRs.

9:10 KEYNOTE PRESENTATION: New GPCR Signaling Circuitries: Opportunities for Novel Precision and Immune Therapies
J. Silvio Gutkind, PhD, Professor, Pharmacology, Moores Cancer Center, University of California, San Diego

GPCRs are widely dysregulated in cancer, and yet largely underexploited in oncology. GPCRs and G proteins are mutated in >25% of human neoplastic diseases, and aberrantly expressed in multiple human malignancies. Emerging evidence supports that some of the most prevalent human cancers deploy GPCR oncocrine networks to promote tumor growth, dissemination, and immune evasion. How targeting GPCRs and their regulated signaling circuitry can be exploited for the development of novel precision cancer treatments and to increase the response to new immunotherapies will be discussed.

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
10:25 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. 

10:55 Development of “Plug and Play” Fiducial Marks for Structural Studies of GPCR Signaling Complexes by Single-Particle Cryo-EM
Somnath Mukherjee, PhD, Research Professional, Biochemistry & Molecular Biology, University of Chicago

Synthetic antibody (sAB)-based fiducial marks were generated by phage display to G-protein receptor kinase 1 and the two G-protein families: Gi and Gs for structure determination of GPCR-signaling complexes by single particle cryo-EM. Several cross-reactive sABs were identified which can be used across all subclasses in a “plug and play” fashion. EM data indicated that these sABs provide effective single and dual fiducials for multiple GPCR signaling complexes.


GPCR-Targeted Antibodies in Hypertensive Diseases

Meredith 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.

Jim Freeth, PhD, Co-Founder & Director, 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.

12:25 pm Session Break
12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:05 Refreshment Break in the Exhibit Hall with Poster Viewing


1:50 Chairperson's Remarks

Jun Chen, PhD, MBA, Senior Scientist, Biochemical and Cellular Pharmacology, Genentech



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

Robert Neff, PhD, Senior 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.

2:25 Novel Binding Strategies for Sodium Channel Targets
Bonnie Ann Wallace, PhD, Professor, Institute of Structural and Molecular Biology, Birkbeck College, United Kingdom

Voltage-gated sodium channels enable translocation of sodium ions across cell membranes, playing crucial roles in electrical signaling in different tissues. Sodium channel mutations give rise to neurological and cardiovascular diseases; hence they are important targets for pharmaceutical drugs. Identifying existing drugs approved for use in humans and repurposing them for treatment of diseases may provide a rapid way forward for new therapeutic applications.

2:55 Sponsored Presentation (Opportunity Available)
3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
4:05 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.

4:35 Antisense Oligonucleotides Targeting Ion Channels for Pain
Owen McManus, PhD, CTO, Q-State Biosciences

Genetic data provides a rationale for targeting SCN9a, a voltage-gated sodium channel, as a step in developing novel therapeutics for severe and chronic pain. Q-State has designed antisense oligonucleotides (ASOs) targeting SCN9a and other pain-related voltage-gated sodium channels. The ASOs were characterized using qPCR and an all-optical electrophysiology (Optopatch) screening platform to measure functional effects in recombinant cells expressing SCN9a, primary sensory neurons and iPS-derived sensory cells.  

5:05 Transition to Breakout Discussion Groups
5:15 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. Visit the conference website for discussion topics and moderators.
6:15 Welcome Reception in the Exhibit Hall with Poster Viewing (Sponsorship Opportunity Available)
7:15 Close of Day

Thursday, September 17

7:30 am Registration and Morning Coffee
8:00 Chairperson's Remarks

Zachary Britton, PhD, Scientist, Antibody Discovery, AstraZeneca


8:05 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.


8:35 The Molecular Architecture of GABAergic Synapses
Josh Smalley, PhD, Postdoctoral Scholar, Neuroscience, Tufts University

γ-aminobutyric acid receptors (GABAARs) are Cl- -preferring ligand-gated ion channels that mediate fast (phasic) synaptic inhibition and tonic (sustained) inhibition in the adult brain. They are important drug targets for benzodiazepines, intravenous anesthetics, and neurosteroids. I will present recent work involving the development of large data-rich 'omic' technologies and bioinformatic analyses with the aim of discovering novel targets for neurological diseases.

9:05 Sponsored Presentation (Opportunity Available)
9:35 Coffee Break in the Exhibit Hall with Poster Viewing

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.


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.

11:20 Enjoy Lunch on Your Own
11:20 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.


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
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 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

Choose 2 Short Courses and 2 Conferences/Training Seminars
Sept. 15 Short Course: SC2: Best Practices for Targeting GPCRs, Ion Channels, and Transporters with Monoclonal Antibodies
Sept. 16-17 Conference: Antibodies Against Membrane Protein Targets – Part 1
Sept. 17 Dinner Short Course: SC10: GPCR Structure-Based Drug Discovery
Sept. 17-18 Conference: Antibodies Against Membrane Protein Targets – Part 2