Original Agenda
We are actively working with our speakers to confirm their availability for the virtual event. Initial response from our speakers has been very positive, and we are optimistic we will have the new programs ready to share here soon.

engineering antibody drug conjugates track banner

The Engineering Antibodies program continues the quest to present the latest antibody design for better binding and affinity, and explore techniques and approaches to engineer proteins and antibodies for challenging membrane proteins, to cross the BBB, as well as for novel therapies. Computational and sequencing approaches to help further the understanding of the sequence and structure-function of molecules, will also be explored.

Wednesday, 11 November

07:45 Registration and Morning Coffee

DESIGNING ANTIBODIES FOR BETTER BINDING, AFFINITY AND TARGETING

08:30

Chairperson's Opening Remarks

Sebastian Kobold, MD, Professor, Clinical Pharmacology, Klinikum der Universität München
08:35 KEYNOTE PRESENTATION: Antibody Discovery Is More than Just Binders
Ruud M. De Wildt, PhD, Director & Biopharm R&D Head, Lead Discovery, GlaxoSmithKline

This talk will provide an overview of how current antibody technologies have revolutionised the way patients are being treated. This revolution means that fully human high-affinity antibodies are now routinely selected from many different in vitro display or in vivo transgenic platforms. This talk will also give an overview of GSK's antibody discovery platforms and processes and will be exemplified with cutting-edge antibody engineering and optimization approaches which, combined with early developability screening techniques, identify antibodies with desirable properties for useful therapeutic approaches.

09:05 Design and Evaluation of pH-Selective Antibodies Targeting the Acidity of Solid Tumors
Traian Sulea, PhD, Principal Research Officer, Human Health Therapeutics Research Centre, National Research Council Canada

Development of monoclonal antibodies as anticancer agents requires optimization of their safety for use in humans. Among optimization avenues for specific tumor targeting is the slightly higher acidity of solid tumors relative to normal tissues. A structure-based computational approach was applied to engineer antibody fragments with selective binding in an acidic environment relative to physiological pH. Designed full-size antibodies exhibit binding and functional selectivities between tumor and normal cell models.

09:35

Domain Antibody Libraries for Rapid Binder Discovery

Franck Perez, PhD, Director, Biology and Cancer Unit, CNRS, Institut Curie

While in vivo immunization remains the main source of antibody identification, progress in gene synthesis opened up the development of fully synthetic libraries. We designed several humanized single-domain scaffolds and generated high-diversity libraries that can be screened by phage display. We will show here that such libraries enable the fast identification of highly specific antibodies that can be used to identify novel tumor antigen, stain or destroy cancer cells.

Jianxin Duan, Fellow, Applications Scientist, Schrödinger GmbH

Introducing mutations to modulate protein thermostability or binding affinity to another protein is a common strategy in protein engineering. Accurate in silico prediction methods can drastically reduce experimental effort. The ability of free energy perturbation (FEP) to accurately predict the small molecule-protein relative binding affinity has been repeatedly demonstrated. In this presentation we will show that FEP is also highly accurate in predicting protein thermostability as well as the protein-protein relative binding affinity. 

 

10:35 Coffee Break in the Exhibit Hall with Poster Viewing
11:15 Discovery and Affinity Maturation of a First-in-Class Inverse Agonist GPCR mAb
Joseph Illingworth, CSO, DJS Antibodies

I will describe the discovery and potency optimisation of the first functional mAb to a clinically validated, but intractable non-chemokine GPCR. This involved overcoming the traditional problems with mAb discovery against integral membrane protein: lack of high quality, pure recombinant protein antigen; and the low quality of tool reagents. Our approach incorporated a novel immunization technology, rational design, and mammalian display techniques to obtain a highly functional candidate mAb.

11:45 Antibodies Exhibit Multiple Paratope States That Can Differ in VH-VL Domain Orientations
Klaus R. Liedl, PhD, Professor & Head, General, Inorganic & Theoretical Chemistry, University of Innsbruck

In contrast to the prevalent static view of the binding interface, we demonstrate a dynamic perspective not only of the paratope, but of whole Fvs and Fabs. We show that antibodies exist as ensembles of paratope states. These paratope states are defined by a characteristic combination of CDR loop conformations and interdomain orientations. They interconvert into each other in the micro-to-millisecond timescale by correlated loop and interdomain rearrangements. We demonstrate that crystal packing effects can distort the paratope state and thus, result in misleading X-ray structures. By advancing the repertoire of cutting-edge simulation techniques, for the first time we achieve a complete description of conformations, thermodynamics, and kinetics of the whole binding paratope in solution. These findings have broad implications in the field of antibody design and in the development of biotherapeutics, as they provide a new paradigm in the understanding of CDR-binding loop states, antibody-antigen recognition, relative VH and VL interface angles, and elbow-angle distributions and their respective dynamics. Preliminary findings are already published in six manuscripts, but a considerable number of further publications is upcoming. These upcoming publications will also address issues like inter-loop correlation and the relationship of Fv-interface dynamics with loop rearrangements.

12:15 Sponsored Presentation
14:15 Session Break

NOVEL APPROACHES TO ANTIBODY DISCOVERY & DESIGN

14:30

Chairperson's Opening Remarks

Ruud M. De Wildt, PhD, Director & Biopharm R&D Head, Lead Discovery, GlaxoSmithKline
14:35

Second-Generation Droplet Microfluidic Platforms for Functional Phenotypic Antibody Screening

Christoph Merten, PhD, Professor, Bioengineering, Laboratory of Biomedical Microfluidics (LBMM), Swiss Federal Institute of Technology Lausanne (EPFL)

We have developed second-generation droplet microfluidics platforms for antibody discovery. These enable fully quantitative screening of secreted IgGs for therapeutic effects on target cells. In this talk, I will give an overview on how these conceptual advantages can be exploited for the identification of antibodies modulating GPCRs, antibodies inhibiting pathogens, or even for the generation of producer cells with increased secretion rates.

15:05

Tailored On-Demand Therapeutics: Changing the Future Treatment Landscape with de novo Protein Design

Daniel-Adriano Silva, PhD, Vice President, Head of Research and Co-Founder, Neoleukin Therapeutics, Inc.

Engineering of de novo proteins has the revolutionary potential to transform the field of therapeutic development, from traditional molecule discovery to a purposeful, ad hoc, molecule engineering. Although still in its early phase, the first examples of this new approach are already showing tangible results that hint at its enormous potential to deliver the next generation of therapeutics, tailored on demand to treat disease. I will illustrate the concept with a few of our recent research developments.

15:35 Refreshment Break in the Exhibit Hall with Poster Viewing

EMERGING ANTIBODIES AND NOVEL PLATFORMS

16:15

Bispecific Antibody-Activated Synthetic Agonistic Receptors as a Novel Modular Platform for Cellular Therapies

Sebastian Kobold, MD, Professor, Clinical Pharmacology, Klinikum der Universität München

Cellular therapies show high promise for the treatment of cancer and are part of the standard of care in some lymphoma and leukemia types. There, cell therapies come with two major limitations which are toxicities due to uncontrolled T cell activation and disease escape driven by antigen loss or down regulation. We have recently developed a novel modular cell therapy platform constituted of fully synthetic inert proteins introduced into T cells that can only be triggered through antibodies specific for said fusion proteins and bound to the tumor cell. This platform is actionable, controllable, and modular, as targeting can be altered by changing the bispecific antibody to be used. I will present data describing the properties of the platform and supporting its use for cancer treatment, warranting its further clinical translation.

16:45

Discovery to Preclinical Development of apoC3 SIMPLE Antibodies

Karen Silence, Project Leader, argenx

STT-5058 is an anti-apoC3 SIMPLE antibody targeting novel and unique epitopes on apoC3- a key molecule in dyslipidemia management. The antibody has recycling properties that are pH-dependent developed with the aim of clearing apoC3-containing lipoproteins, thereby lowering triglycerides and the potential for increasing clearance of atherogenic remnant lipoproteins. During this presentation we will discuss the discovery, engineering and pre-clinical development of STT-5058.

17:15

Multispecific MATCH Antibodies Enable Novel Therapeutic Strategies By Targeting Synergistic Immunomodulatory Functions to the Tumor Microenvironment

David M. Urech, PhD, CEO & CSO, Numab Therapeutics AG

Numab’s MATCH platform was exploited for the generation of a monovalent trispecific 4-1BB/PD-L1/HSA MATCH3 molecule (NM21-1480) that agonizes 4-1BB on anti-cancer T cells, conditionally upon binding to and blockade of PD-L1 on tumor cells. NM21-1480 shows superior efficacy over conventional CPI therapies and avoid dose limiting toxicities of systemic 4-1BB agonism. Further, tetra-specific MATCH4 molecules are exploited to improve on safety and efficacy of conventional bispecific strategies.

17:45 Networking Reception in the Exhibit Hall with Poster Viewing
18:45 Problem Solving Breakout Discussions*

*Topics to be announced.

19:45 End of Day

Thursday, 12 November

08:00 Registration and Morning Coffee

ANTIBODIES ENGINEERED TO CROSS THE BBB

08:30

Chairperson's Opening Remarks

Catherine Hutchings, PhD, Independent Consultant, United Kingdom
08:35 The Transport Vehicle: Crossing the Blood-Brain Barrier for Neurotherapeutics
Joy Yu Zuchero, PhD, Sr Scientist & Pathway Leader, Denali Therapeutics Inc

Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB). We have developed a transport vehicle (TV) by engineering the Fc fragment to exploit receptor-mediated transcytosis by binding to a highly expressed BBB cell target. The TV platform significantly improves CNS uptake of peripherally administered protein therapeutics and results in sustained pharmacodynamic responses in both mice and non-human primates.

09:05

Transporting Antibodies over the Blood-Brain Barrier and Therapeutic Effects on Neurodegenerative Diseases

Greta Hultqvist, PhD, Associate Senior Lecturer, Pharmaceutical Biosciences, Uppsala University

The blood-brain barrier (BBB) severely limits the number of antibodies that reaches the brain, impeding the development of immunotherapy. We have developed a transporter for antibodies, which increases the brain uptake 80 times and enables novel treatment strategies. Here I illustrate this by showing data from a treatment study where we have managed to decrease amyloid amounts in the brain of mice with Alzheimer's disease. 

09:35

Transferrin Receptor-Mediated BBB Shuttling Antibodies Based on VNARs

Pawel Stocki, PhD, Director, Research, Ossianix Inc.
  • Advantages of VNARs as brain shuttles
  • Mechanistic requirements for efficient brain transport
  • Wide range of payload delivery including peptides, enzymes and antibodies
10:35 Coffee Break in the Exhibit Hall with Poster Viewing

ANTIBODIES AGAINST MEMBRANE PROTEINS

11:15

Molecular Insight into Recognition of the CGRPR Complex by Migraine Prevention Therapy, Aimovig (Erenumab)

Fernando Garces, PhD, Senior Scientist and Group Lead, Protein Engineering, Therapeutics Discovery, Amgen, Inc.

Erenumab is the only US FDA-approved mAb therapy against the CGRP receptor (CGRPR) for the prevention of migraine, and also against a G-protein-coupled receptor (GPCR). Here, we report the architecture and functional attributes of erenumab critical for its potent antagonism against CGRPR. The crystal structure of erenumab, in complex with CGRPR, reveals a direct ligand-blocking mechanism, enabled by a remarkable 21-residue-long CDR-H3 loop that projects deep into CGRPR. Such structural insights reveal the drug action mechanism of erenumab and shed light on developing antibody therapeutics targeting GPCRs.

11:45 Road to the First GPCR Agonist Antibody and Future Prospects
Yanbin Ma, Drug Discovery Head, Innovation Center, Shanghai Benemae Pharmaceutical Corp.

Agonists for G-protein-coupled receptors (GPCRs) in treating diseases are needed, whereas it remains a big challenge in developing antibody agonist as a novel modality targeting GPCR. Here, we report a full agonist, JN241-9, for human apelin receptor (APJ), realized by structure-guided conversion of single-domain antibody antagonist, JN241. 

13:15 Dessert Break in the Exhibit Hall with Poster Viewing
14:00 Close of Engineering Antibodies
17:00 Dinner Short Course Registration
17:30 Recommended Dinner Short Course*
SC7: Antibody Mutagenesis and Selection Strategies for Therapeutic Success

*Separate registration required. See short course page for details.