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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THURSDAY 3 NOVEMBER
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.
13:35 KEYNOTE PRESENTATION:
Protein Engineering for New Modes of Action
Andreas 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 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 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
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FRIDAY 4 NOVEMBER
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 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 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 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 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 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 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 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 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 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
Stanislas 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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