Engineering Bispecifics banner

Exciting progress is being made in engineering for more targeted bispecific therapeutics that have optimal stability and half-life, and proven functionality. Balancing the affinity of the two arms of the bispecific, especially for CD3 targeting products, is seen as a common challenge and efforts are clearly underway to overcome this for enhanced targeting and minimal toxicity. Engineering Bispecifics will present novel approaches to optimize the product and address the challenges.

Final Agenda


13:00 Registration (Foyer C)

13:15 Dessert Break in the Exhibit Hall with Poster Viewing (Pavilion 1)

Auditorium VII

14:00 Chairperson’s Opening Remarks

Javier Chaparro-Riggers, PhD, Senior Director, Protein Engineering, Pfizer, Inc.

14:05 KEYNOTE PRESENTATION: Novel T Cell Engagers for Targeted Recruitment of Effector Cells to Tumors

Reiter_YoramYoram Reiter, PhD, Head, Molecular Immunology, Technion-Israel Institute of Technology

We have developed a new class of recombinant chimerical molecule that serve as T cell engagers to re-direct potent immune effector functions to specifically kill tumor cells. These T cell engagers are based on the genetic fusion of antibody fragments, specific for tumor cell surface antigens to monomeric HLA molecules that carry immunodominant peptides that can recall potent effector T cells. The molecular feature of these molecules/approaches and their in vitro and in vivo activities will be described.

14:35 Engineering of a T-Cell Dependent Bispecific to Broaden the Therapeutic Index for Solid Tumors

Spiess_ChristophChristoph Spiess, PhD, Senior Scientist, Antibody Engineering, Genentech, Inc.

I will present the engineering of the bispecific to achieve selective binding to tumor cells and provide data demonstrating improved tumour infiltration in vitro and in vivo and preclinical safety.

15:05 Computational Framework to Address Liabilities in Biotherapeutics

Jianxin Duan, PhD, Fellow AppScie, Schrodinger GmbH

As antibody generation produces an increasing number of leads, it is crucial to detect possible protein liabilities early. In particular, protein aggregation, viscosity and solubility have been identified the most serious issues. Here we present an aggregation propensity scoring function, AggScore which considers both hydrophobicity and polarity of the protein structures and BioQSPR that uses machine-learning techniques to address these complex issues. We demonstrate a computational workflow that can be applied to triage candidates rapidly.

15:35 Networking Refreshment Break (Foyer D)

16:00 Creating a Novel T-Cell Engaging Bispecific Antibody Platform: Fine Tuning Anti-Tumor Activity with Sequence-Based Discovery and Machine Learning

Trinklein_NathanNathan Trinklein, PhD, VP, Discovery, Teneobio

Using a multiple myeloma tumor cell line along with primary human PBMCs, we demonstrate a spectrum of in vitro tumor cell killing activity with varied levels of cytokine release using our bispecific molecules with diverse CD3 binding activities. In summary, we have created a T-cell engaging bispecific antibody platform with tuned T-cell agonism that can be used to optimize the therapeutic index for a variety of tumor antigens.

16:30 Developing Humabody VH Therapeutics for Immuno-Oncology

Legg_JamesJames Legg, PhD, Vice President, R&D, Crescendo Biologics

This presentation describes our approach to developing immune-oncology therapeutics, in particular Humabody VH products, small highly adaptable multi-functional proteins which can be developed into differentiated therapeutics with excellent characteristics for tumour targeting. It includes the development of a Biparatopic PD-1 inhibitor showing efficacy in a Pembrolizumab insensitive in vivo model, a Bispecific PD-1, LAG3 inhibitor and a targeted IO approach in which T-cell co-stimulation is focused away from the periphery and into the tumour microenvironment.

17:00 End of Day

17:00 Dinner Short Course Registration* (Foyer C)

17:3020:30 Dinner Short Courses

Recommended Short Courses*

SC8: Selection, Screening and Engineering for Affinity Reagents - View Detailed Agenda

Julia Neugebauer, PhD, Director, MorphoSys AG

Birgit Dreier, PhD, Senior Scientist and Group Leader HT-BSF, Plückthun Lab, University of Zurich

Biologics such as recombinant antibodies and alternative binding scaffolds are routinely used in a wide variety of applications from basic research to clinical indications. This success has led to the development of a vast number of different selection, screening and engineering technologies for these molecules. This short course will give a comprehensive overview on different display technologies as well as screening approaches for the selection of specific binders. In addition, it will discuss engineering strategies including affinity maturation and how to implement these strategies. Classical antibodies and antibody fragments as well as alternative binding scaffolds such as DARPins will be covered.

SC10: Engineering of Bispecific Antibodies - View Detailed Agenda

Nicolas Fischer, PhD, Head, Research, Novimmune SA

Michela Silacci, PhD, Director, Discovery Research, Covagen AG, part of J&J

By attending this interactive workshop, you will learn about the various approaches used for the engineering of bispecific antibodies and bispecific scaffold-based binding proteins. Different technologies will be compared, and examples for applications of bispecific antibodies in drug development will be presented with a focus on candidates that are currently being evaluated in clinical trials. Opportunities and challenges as well as current trends in the field of bispecific antibodies will be discussed.

*Separate registration required.


08:00 Registration (Foyer C) and Morning Coffee (Foyer D)

Auditorium VII

08:30 Chairperson’s Remarks

Martin Bader, PhD, Head, Biochemical and Analytical Research, Pharma Research and Early Development, Roche

08:35 Glyco-Optimization of Antibodies Targeting Immune Checkpoint Molecules: Case Studies of an Agonist and an Antagonist

Goletz_ChristophChristoph Goletz, PhD, Associate Director, Preclinical Pharmacology & Cancer Immunology, Glycotope GmbH

Glyco-engineering is an established strategy to improve tumor antigen-targeting antibodies, e.g. anti-CD20, anti-EGFR, regarding their ADCC activity. In two case studies of an agonistic anti-CD40 and an antagonistic anti-PD-L1 antibody, we show that glyco-optimization can also be applied to enhance activity of antibodies targeting immune checkpoint molecules.

09:05 Development of a Novel Fc Heterodimerization Technology

Richter_FabianFabian Richter, PhD, Post-Doc, Biomedical Engineering, Cell Biology and Immunology, University of Stuttgart

The innovative heterodimerization technology “Fc1k” (Fc-one-kappa) was created and used for the generation of monovalent as well as polyvalent and multi-specific antibody-like molecules. We demonstrated the applicability in a monovalent Fv-Fc1k format, used for cytokine receptor blockade and in a bispecific scFv2-Fc1k molecule, simultaneously targeting two antigens. This novel platform technique provides for covalent heterodimerization of immunoglobulin domains, based on fully human and naturally occurring sequences.

09:35 Identification of a PD-L1 Binding Fcab: A Potent Inhibitor of Immunosuppressive Signals

Munoz-Oleya_JoseJose Munoz Olaya, PhD, Principal Scientist, Drug Discovery, F-star

Checkpoint inhibitors have been very popular and successful targets in the field of immuno-oncology. Here we describe the isolation of an Fcab, an antibody Fc domain modified to bind to a target, specific to PD-L1. The Fcab exhibits high affinity to human PD-L1 that translates into strong potency in cell-based functional assays. An anti-murine surrogate molecule, with similar potency, also exhibits activity in an MC38 syngeneic tumour model. This activity is improved when the Fcab is paired with Fabs targeting other immune checkpoint regulators.

10:05 Networking Coffee Break (Foyer D)

10:35 Antibody Transport Vehicle (ATV): A Novel Brain Delivery Platform

Dennis_MarkMark S. Dennis, PhD, Fellow, Denali Therapeutics

The Antibody Transport Vehicle (ATV) enables the delivery of large molecule therapeutics to the brain for the treatment of neurological diseases. The ATV platform contains an engineered Fc domain that binds the transferrin receptor and utilizes receptor-mediated transcytosis to cross the BBB. Transport in nonhuman primates was assessed by the inhibition of β-secretase 1 (BACE1) in brain which was robustly inhibited by ATV:BACE1 leading to a sustained reduction in amyloid beta levels.

11:05 Turning Affibody Molecules into Efficient Peptide Binders by Dimerization

Lofblom_JohnJohn Lofblom, PhD, Associate Professor, Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology

Affibody molecules are small three-helical affinity proteins. Generating binders for the amyloid beta peptide yielded a variant with 20-pM affinity, and with a unique 2:1 stoichiometry mode of binding as well as structural rearrangements in both the affibody domains and the amyloid beta peptide that is sequestered in a tunnel-like cavity. Engineered binders for other peptides show similar structural rearrangements and mode of binding, indicating that the new dimeric scaffold is well suited for such molecular recognitions.

11:35 Industrializing IO Therapeutic Discovery Platforms: Multispecifics, Engineered TCRs and CARs

Christoph Freiberg, PhD, Head, Science, Biologics, Genedata

Novel classes of bio-molecules are currently evaluated for their use in cancer immunotherapy. Bi- and multi-specific antibodies, Ab-cytokine fusion proteins, non-Ig scaffolds, chimeric antigen receptors (CARs), engineered TCRs and TCR-based bispecific constructs promise significant advantages. However, these highly engineered molecules pose new challenges in design, engineering, cloning, expression, purification, and analytics. We present an infrastructure that addresses these challenges and enables the industrialization of these various novel therapeutic platforms.

12:05 Problem-Solving Breakout Discussions with a Light Snack (Foyer E&F)

Key Features of Bispecific Antibody Platform

Moderator: Ulrich Brinkmann, PhD, Expert Scientist, PRED, Roche

  • Best use of Bispecific antibodies
  • Bispecific antibody platforms, strengths and challenges
  • Criteria for selecting bispecific antibody leads
  • Emerging issues with bispecific antibodies

Strategy for Engineering and Design of Bispecific TCR-Based Products

Moderator: Yoram Reiter, PhD, Head, Molecular Immunology, Technion-Israel Institute of Technology

  • The differences and similarities in TCR-based bispecific vs. conventional antibody-based bi-specific
  • Measures to increase tumor specificity
  • Balancing the affinities of the bispecific tumor antigen and CD3
  • Potential of CD3 bispecifics for the treatment of solid tumors
  • Optimal PK properties for CD3 bispecific products
  • Getting the right potency / toxicity balance

Auditorium VII

13:00 Chairperson’s Remarks

Mark S. Dennis, PhD, Fellow, Denali Therapeutics

13:05 Case Studies on How Digital and Automated Solutions Transform the Discovery and Development of Next-Generation Antibodies

Bader_MartinMartin Bader, PhD, Head, Biochemical and Analytical Research, Pharma Research and Early Development, Roche

We systematically introduced automated and digital solutions along our antibody discovery and development chain. A number of examples will be highlighted that demonstrate how automation and data science speed up 1) developability predictions to enable fast selection of clinical leads, 2) automation during functional characterization, and 3) machine learning during cell line selection and bioprocess modeling. As a consequence, output during the antibody discovery and development phase increases substantially.

13:35 Simultaneous Multiple Interaction T Cell Engaging (SMITE) Bispecifics: Silence and Synergy Through T Cell Costimulation

Colin E. Correnti, PhD, Senior Scientist & Director, Protein Sciences, Clinical Research Division, Fred Hutchinson Cancer Research Center

We are developing pairs of synergistic T cell engagers that simultaneously bind two cancer antigens and two T cell coreceptors. Importantly, each singleton is selected to be inactive until paired, providing T cell costimulation and improved cancer specificity. In this presentation I’ll describe our approach for generating silent and synergistic T cell engagers, highlighting our use of the Trianni™ mouse and automated methods for protein expression and T cell assays.

14:05 Redefinition of ErbB2/3 Tumor Targeting: How to Design Truly Potent Bispecific and Biparatopic Agents

Tamaskovic_RatislavRastislav Tamaskovic, PhD, Head, TC Facility, Senior Scientist, Biochemistry, University of Zurich

Due to adaptiveness of oncogenic networks, tumors readily develop resistance against targeted therapies. Recently, we have described major compensatory routes, which become activated in therapy of ErbB2-positive cancer - and developed a new class of bispecific and biparatopic anti-ErbB2/3 targeting agents endowed with capabilities to overcome the adaptive resistance. Analogously, we build a new platform for tumor RTK fingerprinting aimed at identification of prospective therapeutic leads and truly synergistic combination therapies.

14:35 Productive Common Light Chain Libraries Yield Diverse Panels of High Affinity Bispecific Antibodies

Chaparro-Riggers_XavierJavier Chaparro-Riggers, PhD, Senior Director, Protein Engineering, Pfizer, Inc.

Here we describe the design of a synthetic human antibody library based on common light chains to generate antibodies with biochemical and biophysical properties that are indistinguishable to traditional therapeutic monoclonal antibodies. We used this library to generate diverse panels of well-behaved, high affinity antibodies toward a variety of epitopes across multiple antigens including mouse 4-1BB in order to investigate the therapeutic potential of biparatopic bispecific antibodies.

15:05 DuoBody Technology: A Versatile Platform for Bispecific Antibody Discovery and Development

Hibbert_RickRick Hibbert, MBA, PhD, Assistant Director, Protein Production and Chemistry, Genmab B.V.

The DuoBody® platform represents a versatile, elegant and robust technology for generating bispecific antibodies. The post-production process is based on controlled Fab-arm exchange and yields bispecific antibodies that retain the molecular structure and quality attributes of therapeutic IgGs. The process is robust, high-throughput compatible and shows linear scalability from bench to manufacturing scale. This presentation will highlight recent insights in the preclinical and CMC development of DuoBody products.

15:35 End of Summit