Emerging Indications for Therapeutic Antibodies

Significant scientific advances in the fields of immunology and protein science are driving the development of biotherapeutic drugs in a growing range of therapeutic areas beyond oncology. These advances support the identification of new and unique targets, new approaches to developing biotherapeutics for unserved medical needs, methods of binding to illusive targets and translational science for patient stratification and drug development for niche indications. The PEGS Emerging Indications for Therapeutic Antibodies conference provides a forum for research organizations with diverse portfolios to explore new science and technology in the development of a next generation of safe and effective therapeutics in an important set of emerging indications.

Monday, August 31

AUTOIMMUNITY & INFLAMMATION

9:05 am

Development of a Novel Therapeutic Antibody Drug Conjugate for the Treatment of Autoimmune Disease

Michael McPherson, PhD, Senior Principal Research Scientist, AbbVie

We have developed a plasma-stable antibody drug conjugate (ADC) that has glucocorticoid receptor modulator (GRM) molecules linked to an anti-TNF-α mAb. This ADC is targeted to TNF-α expressing inflammatory cells and internalized into lysosomes where GRM payload is released. This significantly reduces the efficacious GRM dose to below levels that induce undesired side effects. Activity of a surrogate anti-TNF GRM conjugate in inflammatory disease models will be described.

9:25 am

Engineered Antibody Platforms for Receptor Agonism

Greg A. Lazar, PhD, Director & Senior Scientist, Antibody Engineering, Genentech Inc.

The majority of immune agonist antibodies currently in clinical development rely on extrinsic crosslinking by Fc receptors to enable in vivo pharmacologic activity. We have explored multiple technology platforms to enable antibodies to promote receptor signaling without relying on Fc receptor engagement. This talk will describe engineering approaches and considerations, present data demonstrating in vitro and in vivo proof of concept, and discuss biological and clinical context for immunotherapy.

9:45 am

Complement Mediation as a Therapeutic Strategy in Autoimmune and Inflammatory Diseases

Claire L. Harris, PhD, Professor Molecular Immunology, Translational & Clinical Research, Newcastle University

The driving role of complement in a single disease, paroxysmal nocturnal hemoglobinuria, provoked the development and FDA approval in 2007 of eculizumab (Soliris™), an anti-C5 antibody. No other drug has since been approved for any other indication. A high attrition rate in complement drug development means that the unmet need for therapy in many complement-driven diseases remains. I will discuss the challenges associated with therapeutic inhibition of complement, highlighting lessons learnt and hurdles cleared by various different therapeutic approaches.

10:05 am Session Break
10:10 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Greg A. Lazar, PhD, Director & Senior Scientist, Antibody Engineering, Genentech Inc.
Panelists:
Claire L. Harris, PhD, Professor Molecular Immunology, Translational & Clinical Research, Newcastle University
Michael McPherson, PhD, Senior Principal Research Scientist, AbbVie
10:30 am Coffee Break - View our Virtual Exhibit Hall

NEUROLOGY & RARE DISEASES

10:50 am

Dissecting Anti-Beta-Amyloid Clinical Outcomes; Why Do Some Antibodies Appear to Work while Others Don’t?

Charles G. Glabe, PhD, Professor, Molecular Biology & Biochemistry, University of California Irvine

Several active vaccines and monoclonal antibodies have been tested in human clinical trials and despite removing amyloid deposits, only Aducanumab has been reported to slow cognitive decline. Those that failed in clinical trials target plaques that may represent tombstone markers of antecedent amyloid pathology. Antibodies that target oligomers, but do not bind plaques, have not been fully evaluated yet. Anti-amyloid antibodies with these and other novel properties remain to be tested in human clinical trials.

11:10 am KEYNOTE PRESENTATION:

Challenges and Opportunities for Biotherapeutics Discovery and Development in Rare Diseases

Madhusudan Natarajan, PhD, Head, Rare Diseases DDU, Takeda

An ongoing biopharma investment in rare disease research, especially in monogenic disorders, coupled with recent advancements and success stories in genetic therapies have fueled a remarkable proliferation of biotherapeutic development at this intersection of therapeutic area and modality. I will showcase examples of opportunities that this intersection provides to “traditional” protein and antibody biotherapeutic development, as well as the associated challenges with these approaches.

Patricia Odermatt, Senior B Cell Scientist, Antibody Discovery, Aldevron

Genovac Antibody Discovery became the first company to successfully combine three powerful antibody discovery platforms while developing humanized antibodies against SARS-CoV-2 targets. Genovac AbD utilized its proprietary genetic immunization technology, Ligand’s OmniRat platform, and Berkeley Lights’ Beacon platform to develop high-affinity antibodies that recognize viral proteins and are potentially capable of neutralizing SARS-CoV-2.

11:55 am LIVE Q&A: :

Session Wrap-Up

Panel Moderator:
Madhusudan Natarajan, PhD, Head, Rare Diseases DDU, Takeda
Panelists:
Charles G. Glabe, PhD, Professor, Molecular Biology & Biochemistry, University of California Irvine
Patricia Odermatt, Senior B Cell Scientist, Antibody Discovery, Aldevron
12:15 pm Lunch Break - View our Virtual Exhibit Hall

CARDIOVASCULAR & METABOLIC DISEASES

12:45 pm

The Adipocyte as a Source for Novel Targets for Therapeutic Antibodies for Metabolism, Fibrosis and Cancer

Philipp E Scherer, PhD, Prof & Dir, Touchstone Diabetes Ctr, Univ of Texas Dallas

Adipose tissue dysfunction is at the heart of diabetes, fatty liver disease, organ fibrosis and enhanced growth for invading tumor lesions in a variety of cancers. We have targeted two key players in that area, leptin and endotrophin. Neutralizing antibodies against these factors whose production is enriched in metabolically challenged adipose tissue are highly effective in preclinical settings as anti-obesity, anti-diabetic, anti-fibrotic, and chemosensitizing agents in the breast cancer area.

1:05 pm

Generation of Single-Domain Antibody Antagonists and Agonists 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.


 

1:25 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Philipp E Scherer, PhD, Prof & Dir, Touchstone Diabetes Ctr, Univ of Texas Dallas
Panelist:
MeiYun Zhang, PhD, Principal Scientist, Antibody Discovery, Amgen Asia R&D Center
1:45 pm Session Break
2:10 pm Refresh Break - View Our Virtual Exhibit Hall
2:30 pm Problem-Solving Breakout Discussions Part A - View our Virtual Exhibit Hall

This session provides the opportunity to discuss a focused topic with peers from around the world in an open, collegial setting. Select from the list of topics available and join the moderated discussion to share ideas, gain insights, establish collaborations or commiserate about persistent challenges.

TABLE 11: Biotherapeutics for Respiratory Indications

Bas van der Woning, PhD, Research Fellow, argenx BVBA
  • What are the biggest unmet medical needs in respiratory diseases (asthma, cystic fibrosis, COPD, idiopathic pulmonary fibrosis, etc.)
  • Systemic versus local administration of biotherapeutics
  • Challenges of local administration of biotherapeutics
  • Methods to measure an effect on lung function (spirometry, CT, 3He MRI, airway resistance, ect.)
  • Biomarkers (eosinophils, neutrophils, IgE, FeNO, ..any new biomarkers?)

TABLE 12: Antibody Targeting and Delivery Strategies for CNS Indications

Charles G. Glabe, PhD, Professor, Molecular Biology & Biochemistry, University of California Irvine
  • Do antibodies that modulate inflammation or complement activity have potential therapeutic activity in CNS diseases?
  • Does
     immunotherapy hold promise for other amyloid related neurodegenerative
    diseases? If so, is it possible to have a broad spectrum or universal
    antibody for neurodegenerative diseases?
  • What parameters are important for making immunotherapy more effective?
  • Does
     amyloid structural polymorphism mean that immunotherapy needs to be
    personalized according to specific conformational strain?
3:00 pm Refresh Break - View Our Virtual Exhibit Hall
3:20 pm Problem-Solving Breakout Discussions Part B - View our Virtual Exhibit Hall

TABLE 13: Strategies for Modulating, Targeting and Directing T Cell Activity for Therapeutic Gain

Elissa Leonard, PhD, Postdoctoral Fellow, Biomedical Engineering, Johns Hopkins University
  • What are the most viable emerging or established strategies for directing T cell specificity? Engineered TCRs? Expansion of endogenous populations? CARs?
  • Other stimulatory signals that can direct lineage and suppressive/inflammatory activity
  • Engineering or controlling persistence
  • Therapeutic viability in terms of cost and scale
3:50 pm Refresh Break - View our Virtual Exhibit Hall

PLENARY KEYNOTE SESSION

4:10 pm

Chairperson's Remarks

K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
4:15 pm

From Energy to Machine Learning

George M. Church, PhD, Robert Winthrop Professor, Genetics, Harvard Medical School

In 1974, I adapted energy optimization methods for use in models of nucleic acids, protein and their interactions, and then for use in crystallographic refinement. In the last days of the second millennium,
David Baker's team won the Critical Assessment of Structure Prediction (CASP) by an unbelievable margin. Since then, our labs exchanged 3 Ph.D. students (Dantas, Raman, Lajoie), Wannier from Mayo's group, Stranges from Kuhlman, and Mandell from Kortemme. We engineered new sensor proteins for metabolic
engineering, essential proteins with non-standard amino acids for biocontainment, and polymerase-pore fusions
for nanopore sequencing. None of this prepared us for the revolution following Gleb Kuznetsov joining our lab in 2012, joined soon by Surge Biswas, Pierce Ogden, Ethan Alley, and Sam Sinai. Together we abruptly moved to "sequence-only", deep machine learning for protein design -- ranging from fluorescent proteins to AAV capsids to antibodies. When combined
with libraries of millions of designed gene segments from chip-synthesis and rapid testing, each design cycle can take large leaps in sequence space and function space.

4:40 pm

The Case for Intelligent Design in Protein Engineering

Jamie B. Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University

Directed evolution is in its prime, and it is deepening our understanding of biological systems and empowering therapeutic design. Recent breakthroughs in structural biology, computational design, and high-dimensional data analytics afford us the unprecedented opportunity to apply molecular, structural, and computational principles to guide protein engineering, employing a so-called “intelligent design” approach. This talk will highlight how my lab harnesses this interfacial approach to overcome the deficiencies of natural proteins.

5:15 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
K. Dane Wittrup, PhD, CP Dubbs Professor, Chemical Engineering & Bioengineering, Massachusetts Institute of Technology
Panelists:
George M. Church, PhD, Robert Winthrop Professor, Genetics, Harvard Medical School
Jamie B. Spangler, PhD, Assistant Professor, Biomedical Engineering and Chemical & Biomolecular Engineering, Johns Hopkins University
5:35 pm Happy Hour - View our Virtual Exhibit Hall
6:10 pm End of Day

Tuesday, September 1

INFECTIOUS DISEASES

9:25 am

Rapid Capture and Screening of the Native Human Antibody Repertoire for the Discovery of Therapeutic Antibodies

Sarav Rajan, PhD, Senior Scientist, AstraZeneca

The human antibody repertoire is a valuable source of therapeutic grade antibodies. However, identifying the rare B cells expressing these antibodies can be challenging. We have built a platform that uses microfluidics to encapsulate millions of primary B cells into droplets, capturing a paired repertoire that can be screened by phage-display. This presentation will describe the technology and its use in rapidly identifying natively-paired and functional antibodies across multiple campaigns.

9:45 am

Antibody-Based Scaffolds to Activate T Cells Targeting CMV and EBV

Elissa Leonard, PhD, Postdoctoral Fellow, Biomedical Engineering, Johns Hopkins University

CMV and EBV are pervasive, typically asymptomatic viral infections that can be deadly for immunocompromised individuals. Patients suffering from these infections have been successfully treated with transfer of ex vivo expanded virus-specific T cells in clinical trials. This treatment is labor-intensive and highly individualized, limiting broader use. Combining an immunostimulatory IL-2/antibody fusion protein with viral antigens, we are developing an injectable alternative for robust virus-specific T cell activation.

10:05 am Session Break
10:10 am

Engineering Antimicrobial Proteins: Co-Evolutionary Models Aid Molecular Discovery

Benjamin J. Hackel, PhD, Associate Professor, Chemical Engineering & Materials Science, University of Minnesota Twin Cities

Antimicrobial proteins (AMPs) present the opportunity for efficient discovery of potent, selective therapeutics for antibiotic-resistant infection. This presentation will discuss platforms to engineer AMP stability, selectivity, and potency via bioinformatics-guided library design and high-throughput discovery assays. Co-evolutionary models enhanced library strategies to engineer endolysin stability and activity against Clostridium perfringens and Enterococcus. A sequence depletion assay mapped oncocin’s sequence-function relationship. These methods are broadly applicable to protein engineering.

10:30 am Coffee Break - View our Virtual Exhibit Hall

ANTIBODIES TO TREAT ASTHMA

10:50 am

Antibody Pliers: A Novel Antibody MOA for Asthma

James T. Koerber, PhD, Senior Scientist, Antibody Engineering, Genentech, Inc.

The serine protease β-tryptase is an important mediator of the allergic inflammatory responses in asthma. Protease inhibitory antibodies employ a mechanism of action (MOA) in which Fab binding directly or allosterically inhibits the protease. I will discuss a novel inhibitory anti-tryptase antibody with a unique bivalent IgG-driven MOA that reveals a new way in which IgGs can inhibit a target and may provide a new strategy for engineering novel antibodies.

11:10 am

Protein Crystallization Promotes Type 2 Immunity and Is Reversible by Antibody Treatment

Bas van der Woning, PhD, Research Fellow, argenx BVBA

Charcot-Leyden crystals (CLCs) consisting of galectin-10 (Gal10) protein are frequently observed in eosinophilic diseases, such as asthma. We found that CLCs stimulated innate and adaptive immunity and acted as a type-2 adjuvant. Antibodies directed against key epitopes of the CLC crystallization interface dissolved CLCs from patient-derived mucus within hours and reversed crystal-driven inflammation, goblet-cell metaplasia, immunoglobulin E synthesis, and bronchial hyperreactivity in a humanized mouse model of asthma.

11:30 am LIVE Q&A:

Session Wrap-Up

Panel Moderator:
James T. Koerber, PhD, Senior Scientist, Antibody Engineering, Genentech, Inc.
Panelists:
Benjamin J. Hackel, PhD, Associate Professor, Chemical Engineering & Materials Science, University of Minnesota Twin Cities
Elissa Leonard, PhD, Postdoctoral Fellow, Biomedical Engineering, Johns Hopkins University
Sarav Rajan, PhD, Senior Scientist, AstraZeneca
Bas van der Woning, PhD, Research Fellow, argenx BVBA
Jacob Glanville, Founding Partner and CEO, Distributed Bio
11:50 am Session Break
12:15 pm Lunch Break - View Our Virtual Exhibit Hall

OTHER EMERGING INDICATIONS

12:50 pm

Identification of Antibodies that Target the Blood-Brain Barrier

Eric V. Shusta, PhD, Professor, Chemical & Biological Engineering, University of Wisconsin Madison

The blood-brain barrier presents a major obstacle to brain drug delivery. We have developed several different enabling platforms for the identification of antibodies against blood-brain barrier resident receptors that could ultimately be used to ferry drug cargo into the brain. Here we will describe our recent efforts to identify such blood-brain barrier-targeting antibodies.

1:10 pm

The Development of Novel WNT Signal Modulating Platforms and their Initial Application to Study Functions of FZDs in Different Tissues

Yang Li, PhD, Vice President, Biology, Surrozen, Inc.

WNT molecules have the potential to induce tissue regeneration and repair. However, their poor biophysical characteristics and lack of selectivity have hindered their application as therapeutics. We have developed a novel antibody based platform for potent, selective WNT surrogate generation, and identified key requirements for maximal signaling.

1:30 pm LIVE Q&A:

Session Wrap-Up

Panel Moderator:
Eric V. Shusta, PhD, Professor, Chemical & Biological Engineering, University of Wisconsin Madison
Panelist:
Yang Li, PhD, Vice President, Biology, Surrozen, Inc.
1:55 pm Close of Emerging Indications for Therapeutics Antibodies





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