2016 Archived Content

Cambridge Healthtech Institute’s 8th Annual
Engineering Bispecifics

New Approaches and Platform Refinements

3 - 4 November 2016 | EPIC SANA Lisboa Hotel | Lisboa PORTUGAL

Research with experts in the field has revealed huge advances in the Engineering of Bispecifics. Investigators are introducing new platforms and developing established ones. There is a lot of interest in the screening and selection of target pairs that work well together and are an improvement on existing approaches. Engineering for quality is paramount, especially getting the balance right between the two arms of the bispecific. Engineering for manufacturability is also important to avoid aggregation, contaminants and chemical modification of the product.

A new and exciting focus is the topic of epitopes: investigators are examining not just the target but also the epitope which is important for specificity and avoidance of cross-reactivity. Not all epitopes are equally suited and attendees at this event hear about epitopes that are best for the target site and how they can be detected.

Final Agenda

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Recommended Short Course*

SC2: Mutation and Selection Strategies beyond Affinity Optimisation

*Separate registration required.


12:30 Registration

13:00 Dessert Break in the Exhibit Hall with Poster Viewing


13:30 Chairperson’s Opening Remarks

Christoph Spiess, Ph.D., Senior Scientist, Antibody Engineering, Genentech, Inc.

Protein Engineering for New Modes of Action

Andreas_PlückthunAndreas Plückthun, Ph.D., Director and Professor, Biochemistry, University of Zurich

The engineering of very robust binding proteins gives new opportunities for achieving novel modes of action of biotherapeutics. These can exploit a very strict control of receptor geometries, the opportunity to attack intracellular targets and the opportunity to engineer cell-specific virus entry. The basis for these development is a reliable engine to generate high-affinity specific binding proteins.

14:20 Pfizer’s T Cell Engaging Full Length Bispecific Antibody Platform: From Bench to NHS

Javier Chaparro-Riggers, Ph.D., Senior Director, Protein Engineering, Rinat Pfizer, Inc.

The recent clinical success of blinatumomab (anti-CD19/CD3) spurred the development of a variety of T cell engaging bispecific antibody architectures. Pfizer developed a T cell engaging antibody platform, which allows the formation of full length human IgG1 and IgG2 antibodies in vitro or in vivo. The effect of IgG isotype and affinities of the T cell- and tumor antigen-targeting arm were explored and optimized.

14:50 Computational Approaches in Antibody Design: Identifying and Reducing Liabilities early in the Discovery Process

David_PearlmanDavid Pearlman, Ph.D., Senior Principle Scientist, Schrödinger

Computational tools that can be used in the optimization process for antibody drug candidates have greatly improved in the past. These tools are finding increasing acceptance for liability assessment and reduction in the discovery process. We describe how these calculations can be utilized for workflowed triage among multiple candidates, and how tools such as FEP are used to suggest sequence engineering that can ameliorate identified liabilities such as aggregation propensity while maintaining affinity and stability.

15:20 Refreshment Break in the Exhibit Hall with Poster Viewing


16:05 Engineering of CD3 Bispecific FynomAbs

Julian_BertschingerJulian Bertschinger, Ph.D., Vice President, Janssen R&D, Managing Director, Covagen

I will describe the development of bispecific FynomAbs by fusing human Fynomer binding proteins to antibodies, resulting in bispecific protein therapeutics with novel modes-of-action and enhanced efficacy for the treatment of inflammatory diseases and cancer. We will present case studies demonstrating that FynomAbs with tailored architecture overcome limitations encountered with other therapeutic protein formats, such as suboptimal efficacy of lack of tumour selectivity.

16:35 High Affinity T Cell Receptor-Based Bifunctional Biologics for Redirected Tumour Killing

Milos Aleksic, Ph.D., Team Lead, Protein Engineering, Immunocore

ImmTACs are bispecific reagents that target tumours via a soluble monoclonal TCR with exceptionally high sensitivity and specificity and redirect host polyclonal T cells via an anti-CD3 antibody fragment. The selection and validation of appropriate target antigens and the testing of ImmTACs for specificity is critical. Using appropriate tumour and primary human cell lines, the in vitro pre-clinical package can be predictive of in vivo clinical observations.

17:05 End of Day

17:00 Dinner Short Course Registration

Recommended Dinner Short Course*

SC6: Engineering of Bispecific Antibodies

*Separate registration required.

Day 1 | Day 2 | Speaker Biographies | Download Brochure


08:00 Registration and Morning Coffee


08:30 Chairperson’s Remarks

Ulrich Brinkmann, Ph.D., Expert Scientist, Roche Innovation Center

08:35 Epitopes Matter: Strategies to Generate and Analyse Binders to Different Epitopes

Jonas_SchaeferJonas Schaefer, Ph.D., Head, High-Throughput Binder Selection Facility, Biochemistry, University of Zurich

Several characteristics determine the true value and potential of affinity reagents for most applications. However, while amongst other the lead candidate’s affinity can be matured after it has been identified, scientists still are not able to routinely and reliably design these binders for specific epitopes. Thus, special considerations have to be taken into consideration both in the selection and screening processes, which will be presented in this presentation.

09:05 Engineered Fab Domains Promote Efficient Production of Bispecific Antibodies in a Single Cell

Christoph_SpiessChristoph Spiess, Ph.D., Senior Scientist, Antibody Engineering, Genentech, Inc.

Bispecific antibodies have gained increased relevance in research and therapeutic settings despite the complexities in their production and challenges in finding the right combination. The presentation will discuss strategies and consideration to screen for the best bispecific antibody pair. In addition, a novel approach to produce a bispecific antibody with natural surface architecture in a single cell will be discussed. The technology now simplifies bispecific production for research and development.

09:35 A Novel Highly Versatile Multi-Specific Antibody Format

Sebastian Meyer, Ph.D., Head, Biochemistry, Numab AG

We present the MATCH, a novel modular antibody format that utilises a pair of split variable domains to drive defined assembly of heterodimeric complexes with up to six specificities. This architecture offers the unique advantage of rapidly screening permutations of binder panels to identify ideal combinations of affinities, potencies and specificities in the final molecular format. This format offers unprecedented opportunities for fine-tuning binding properties for targeting complex pathologies.

10:05 Coffee Break in the Foyer with Poster Viewing


10:35 CrossMAb Version 2: A Versatile Toolbox for Bispecific Antibody Engineering

Joerg_RegulaJoerg Thomas Regula, Ph.D., Head, Functional Characterisation, Large Molecule Research, Roche Pharmaceutical Research and Early Development

The CrossMAb technology (Schäfer et al., 2011) can be used to generate a bispecific antibody from two independent parental antibodies by immunoglobulin domain exchange. Additional modifications can be introduced in these different CrossMAb designs. This enables their use as well suited building blocks for the generation of bispecific antibodies with 1+1, 2+1 or 2+2 target binding sites.

11:05 Efficient Generation of Bispecific Mouse Antibodies for Preclinical Investigations

Aran_LabrijnAran F. Labrijn, Ph.D., Principal Scientist, Antibody Sciences, Genmab BV

Complex therapeutic concepts are often studied using (surrogate) mouse antibodies in immunocompetent mice to ensure optimal interaction with tumour associated immune cells and the microenvironment. We recently described controlled Fab-arm exchange (cFAE) as a versatile and robust method for the generation of therapeutic human IgG1 bispecific antibodies (bsAb). To facilitate the study of dual-targeting concepts in immunocompetent mice, we have now applied and optimised our method for the efficient generation of murine bsAbs.

11:35 Platform Refinements for Bispecifics for Oncology Targets

John_de_KruifJohn de Kruif, Ph.D., CTO, Merus

Many different bispecific antibody formats have been designed with only few of these reaching the clinic. Extensive engineering of antibodies often results in molecules that behave poorly with respect to fundamental drug-like properties such as production, stability and half-life. Complex engineering of these molecules blocks screening of large panels of bispecific antibodies for functional activity. We present a bispecific antibody platform that combines an efficient discovery engine with a stable antibody format and industry-scale manufacturing.

12:05 Achieving Optimal Bispecific Antibody Assembly by Codon De-Optimization

Nicolas Fischer, Ph.D., Head, Researcg, Novimmune SA

Bispecific antibodies often rely on the co-expression of three or more chains, and maximal bispecific antibody production is achieved when their expression is relatively balanced. We have investigated different approaches to control and balance the relative expression of light chains, and the effect on assembly of native bispecific antibodies. We found that codon de-optimization - instead of optimization - of an ever expressed chain led to significant increase in yield. This approach to tune the ratio of different polypeptides can be applied to improve assembly of other protein complexes.

12:35 Problem-Solving Breakout Discussions with a Light Snack in the Foyer

Table 1: Comparing Bispecific Antibody Platforms: Key Features

Moderator: Janine Schuurman, Ph.D., VP, Research, Genmab B.V.

  • Discussing bispecific antibody platform strengths and challenges: focus on discovery and development
  • Discussing criteria for selecting bispecific antibody leads (including understanding the biology)
  • Novel antibody formats for improved therapy
  • Genetic and chemical engineering approaches
  • Increasing potency and decreasing escape and resistance
  • Optimizing the therapeutic window

Table 2: Strategy for Engineering and Design of Bispecific TCR-Based Products

  • Moderator: Julian Bertschinger, Ph.D., VP, Janssen R&D, Managing Director, Covagen
  • How can we increase tumor specificity?
  • What are optimal affinities of the bispecific tumor antigen and CD3?
  • Can we use CD3 bispecifics for the treatment of solid tumors?
  • What is the optimal PK properties for CD3 bispecific products

Table 3: Improved Methods for Binder Screening and Validation

Moderator: Jonas V. Schaefer, Ph.D., Head, High-Throughput Binder Selection Facility, Biochemistry, University of Zurich

  • Pros and cons of various screening assays
  • Significance and validity of different assays
  • Traditional (plate-based) vs. modern (homogeneous) assays
  • Throughput aspects in screening and validation

13:35 Session Break


14:00 Chairperson’s Remarks

Joseph Dukes, Ph.D., Head, Pre-Clinical Biology, Cell Biology, Immunocore

14:05 Using Alphabodies to Generate Bispecifics with Optimal in vitro and in vivo Characteristics

Yvonne_McGrathYvonne McGrath, Ph.D., CSO, Complix NV

CMPX-1023 is an Alphabody that has been engineered to bind the p19 chain of IL-23, a cytokine of therapeutic importance in autoimmune disease. By fusing CMPX-1023 to different anti-TNFα antibodies at various positions, we have generated a panel of therapeutic bispecific proteins. CMC characteristics, in vitro potencies and in vivo pharmacokinetics of this panel of bispecifics will be presented.

14:35 Hapten-Bispecific Antibodies for Drug Discovery and Delivery Applications

Ulrich_BrinkmannUlrich Brinkmann, Ph.D., Expert Scientist, Roche Innovation Center

Many bispecific and engineered antibody derivatives are in preclinical stages for a variety of applications, some in clinical development, and a few are approved. The presentation will provide an overview of the concepts and status of engineered bispecific antibodies at Roche with a focus on novel formats and bsAb-applications for discovery applications. This includes the application of Hapten-binding antibody derivatives for delivery of payloads to, into, as well as across tissues and cells.

15:05 Cellular FRET Assay for the Determination of Simultaneous Binding of Bispecific Antibodies

Stefan_SeeberStefan Seeber, Ph.D., Principal Scientist, Cell Line and Molecule Development, Roche Innovation Center Munich/Large Molecule Research

To demonstrate simultaneous binding to two cell surface expressed receptor targets, we developed a robust, one-vial, FRET-based system, allowing for parallel testing of 2 independent pathways (not necessarily cross-talking). We engineered cell lines expressing the two receptors with FRET tags inserted proximal to the cell membrane. Possible applications as a screening tool or potency assay will be discussed.

15:35 Novel Strategy for a Bispecific Antibody: Induction of Dual Target Internalisation and Degradation

Ji_Min_LeeJi Min Lee, Ph.D., Principal Scientist, Open Innovation Team, Samsung Bioepis

Cancers show well aligned multifaceted properties, and there is cross-talk and convergence of signaling pathways of RTKs. Consequently, many therapeutic interventions have been actively developed to overcome inherent or acquired resistance. To date, no BsAb have shown complete depletion of dual RTKs from the plasma membrane and efficient dual degradation. Leveraging the anti-Met mAb, we generated the BsAbs for Met/EGFR and Met/HER2 to induce an efficient EGFR or HER2 internalisation and degradation.

16:05 Engineering and Manufacturing of Bispecific Antibodies for T-Cell Redirection

Blein StanislavStanislas Blein, Ph.D., Senior Director, Antibody Engineering, Glenmark Pharmaceuticals

Over the past two decades various functional bispecific antibody formats have been designed with only few molecules reaching clinical trials due to an inherent lack of manufacturability. Herein we describe a versatile bispecific antibody format that fits industrial-scale manufacturing processes and enables the rapid design and making of T-cell redirecting molecules. Engineering, preclinical and phase-one manufacturing data will be presented.

16:35 End of Conference

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