2017 Archived Content
In this track, investigators present innovative configurations with optimal geometry and spatial distribution of the two binding sites as well as novel conjugation technology, and stress the importance of the affinity of the individual arms, overall avidity
and format valence. These innovations provide bispecifics with enhanced binding, specificity and efficacy, together with reduced off-target toxicity and adverse effects. In addition, this track features unique modes of action and versatility, and
includes evidence of synergies, together with criteria for selecting and screening bispecific antibody leads and combinations.
Final Agenda
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THURSDAY 16 NOVEMBER
12:30 Registration
13:00 Dessert Break in the Exhibit Hall with Poster Viewing
13:30 Chairperson’s Opening Remarks
Frank S. Walsh, Ph.D., CEO, Ossianix
13:35 Spy and Snoop Superglues to Engineer Diverse Protein and Peptide Architectures
Mark Howarth, DPhil, Associate Professor, Protein Nanotechnology, Biochemistry, University of Oxford
There is need for efficient approaches for new bispecific and polyspecific architectures. We created a peptide (SpyTag) spontaneously reacting with its protein partner (SpyCatcher). Reaction is high-yielding, genetically encodable and specific. SpyTag
generated affibody polymers for cancer cell capture from blood and cyclized enzymes resilient to boiling. I will describe the use of different peptide superglues for programmable synthesis of multi-functional nanobody/affibody teams, to modulate precisely
signaling in cancer cell death.
14:05 TRACS (Trivalent Ab Conjugates): A Plug and Play Multivalent Ab Format
Diego Ellerman, Ph.D., Scientist, Protein Chemistry, Genentech
We describe a novel multivalent format based on protein conjugation (TRACS). The building blocks are mAbs and Fabs with good expression yields and stability. A conjugation site that supports high conjugation rates and an efficient process was identified.
The spatial arrangement of all the Fabs allows their simultaneous binding with reduced steric hindrance. We provide examples of different TRACS that require concurrent binding of all Fabs for their biological activity.
14:35 Computational Advances in Antibody Discovery: Toward Earlier and Better Assessment, Triage and Optimization
Jianxin Duan, Ph.D., Bavaria Application, Scientist Applications, Science Structure-based Applications, Schrödinger
GmbH
In the field of antibody drug discovery, there is growing realization that methods to assess, triage, and avoid liabilities in potential candidates must come early in the discovery process. Recent advances in computational approaches for antibody structure
prediction, identification of protein liabilities (such as aggregation propensity), and in methods for protein engineering hold substantial promise in moving us closer to reaching this goal in an effective and efficient manner.
15:05 Refreshment Break in the Exhibit Hall with Poster Viewing
15:50 Developing Next Generation Biologics Therapies Using a Novel Bispecific Technology FIT-Ig
Chengbin Wu, Ph.D., CEO, EpimAb Biotherapeutics
We have developed a new generation of bispecific antibody technology termed FIT-Ig, which maintains the structural integrity and biological properties of the 2 parental mAbs, and also shows drug-like properties and high productivity in CHO cells. This
unique design of bispecifics does not require any mutations or use of linkers, and is potentially a plug-and-play platform approach for efficient bispecific generation and development.
16:20 Nanofitin-Based Bispecifics Platform
Mathieu Cinier, Ph.D., CSO, Affilogic
Building on antibody expertise, many different bispecific formats were engineered (additional escaping pathway neutralization, recruitment of effectors) but often at the expense of the overall physico-chemical properties of the biologic itself compared
to the state of the art for mAbs. Nanofitins are proposed as a novel bispecific platform, whereby additional targeting specificities are provided with attractive physico-chemical properties.
16:50 End of Day
17:00 Dinner Short Course Registration
17:30 - 20:30 Recommended Dinner Short Course*
SC6: Engineering of Bispecific Antibodies
*Separate registration required
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FRIDAY 17 NOVEMBER
08:00 Registration and Morning Coffee
08:30 Chairperson’s Remarks
Nicolas Fischer, Ph.D., Head, Research, Novimmune
08:35 Structure Guided Specificity Engineering in a MAGE A3 Specific TCR
Stephen Harper, Ph.D., Group Leader, Protein Engineering Research, Protein Science, Immunocore Ltd.
ImmTAC molecules are bispecific therapeutics that use a TCR targeting domain and anti-CD3 specific scFv effector function to re-direct a potent T cell response to kill cancer cells. Here we present an example of structure guided engineering in a TCR targeting
the HLA-A*01 -restricted epitope of MAGE-A3. Mutants were designed to reduce off-target cross-reactivity to a structurally related peptide derived from titin, a protein expressed in cardiac tissue.
09:05 Balancing Selectivity and Efficacy of Bispecific EGFR x c-MET Antibodies and Antibody-Drug Conjugates
Lars Toleikis, Ph.D., Director, Protein Engineering & Antibody Technologies, Merck KGaA
Therapies targeting the tumor-associated antigen epidermal growth factor receptor (EGFR) often suffer from toxicities due to basal EGFR expression in normal tissue. Furthermore, EGFR-directed inhibitors might struggle with limited efficacy because
of c-MET mediated resistance mechanisms. Hence, we aim to construct bispecific EGFR x c-MET antibodies employing affinity-optimized binding moieties to balance selectivity and anti-tumor efficacy and to evaluate their potential for an innovative
antibody-drug conjugate approach.
09:35 A Tale of Two Specificities: The Balancing Act of Tumor-Targeting Selectivity and Therapeutic Index in Bispecific Antibodies
Yariv Mazor, Ph.D., Senior Scientist, Antibody Discovery & Protein Engineering, Medimmune, Inc.
Dual targeting of antigen double-positive cancer cells is believed to enhance therapeutic efficacy, restrict escape mechanisms and increase selectivity, leading to reduced systemic toxicity and improved therapeutic index. However, the interplay of
factors regulating target selectivity is not well understood and often overlooked. We show in vivo that dual targeting alone is not sufficient to endow selective tumor-targeting, and report the pivotal roles played
by the affinity of the individual arms, overall avidity and format valence.
10:05 Coffee Break with Poster Viewing
10:35 KEYNOTE PRESENTATION: Optimizing Delivery of Bispecific Antibodies to the Brain
Frank S. Walsh, Ph.D., CEO, Ossianix
Using in vitro and in vivo phage display technology, we isolated cross species binders to the transferrin receptor 1 (TfR1) from synthetic single domain VNAR libraries. At therapeutic
(2 mg/kg) doses delivered by tail vein injection, high levels (>5% brain/plasma ratio) of the bispecific antibodies were found in the brain after 18 hours. We have now optimized the BBB transfer by mutagenesis of the VNAR CDR3 region and identified
epitopes involved in transfer.
11:05 One Size Does Not Fit All; Opportunities and Challenges of Using Artificial Disulfide Bonds for the Production of Bispecific IgGs
Itai Benhar, Ph.D., Professor, Molecular Microbiology and Biotechnology, Tel-Aviv University
We present a solution for correct pairing of heavy and light chains of bispecific IgGs; an engineered disulfide bond between the antibodies’ variable domains that asymmetrically replaces the natural interchain disulfide bond. A novel approach
for precise evaluation of correct chain pairing by LC-MC-MS combined with chemical crosslinking is presented. Examples will be provided for some of these bsAbs and future directions of the study will be discussed.
11:35 Engineering Proteins of Circular Architecture
Anke Steinmetz, Ph.D., Senior Scientist, Integrated Drug Discovery/Structure, Design & Infomatics,
Sanofi R&D
Design of therapeutic proteins seldom aims at circular architecture. Protein engineers in applied pharmaceutical research avoid conceptually sophisticated structural design due to limitations in time, resources, and the lack of user-friendly, fast,
easy to use, reliable molecular modeling tools for such purposes. We illustrate how we designed a bispecific antibody of circular self-supporting architecture and present implications of circular versus linear domain constellation on biological
effects.
12:05 Sponsored Presentation (Opportunity Available)
12:35 Problem-Solving Breakout Discussions with a Light Snack in the Foyer (View All Breakout Discussions)
Key Features of Bispecific Antibody Platform
Moderator: Nicolas Fischer, Ph.D., Head, Research, Novimmune SA
- Best use of Bispecific antibodies
- Bispecific antibody platforms, strengths and challenges
- Criteria for selecting bispecific antibody leads
- Emerging issues with bispecific antibodies
Balancing Affinity, Avidity and Valency of Bispecifics with Target Selectivity
Moderator: Yariv Mazor, Ph.D., Senior Scientist, Antibody Discovery & Protein Engineering, Medimmune, Inc.
- Limitations of dual target selectivity
- Ways of optimizing the component parts
- How valency can impact on target selectivity
13:35 Session Break
14:00 Chairperson’s Remarks
Mark Howarth, D.Phil., Associate Professor, Protein Nanotechnology, Biochemistry, University of Oxford
14:05 Early Stage Developability Assessment to Enable Bispecific Design
Laura Lin, Ph.D., Senior Director, BioMedicine Design, Worldwide Research & Development, Pfizer, Inc.
The presentation will showcase our strategies of applying early stage developability assessment to enable the design and optimization of bispecific molecules. I will be sharing several case studies highlighting the impact of such assessment on lead
selection and optimization, and predictability of early screens on efficacy, PK, and manufacturability.
14:35 Towards “in Format” Selection and Screening of Bispecific Antibodies
Nicolas Fischer, Ph.D., Head, Research, Novimmune
Optimal geometry of the two binding sites is often important for the function of Bispecific Antibodies. In addition to combinatorial assembly followed by extensive functional testing, we aimed at identifying appropriate binding pairs as early as possible,
i.e. at selection and screening stages. We have developed a dual-display technology that allows the an ‘in format’ preferential enrichment and co-selection of antibody fragments based on target co-engagement. Different modalities to
maximize the throughput of functional screening for BiAb have been implemented to optimize the discovery process.
15:05 Using a Design of Experiments Approach to Identify Critical Residues in FcR Engagement for Both IgG1 and IgG4 Fc-Hexamers
Shirley Peters, Ph.D., Senior Scientist, Protein Sciences, UCB
We have used antibody engineering and recombinant expression to produce Fc with controlled hexa-valency, “Fc-multimer”. Fc-hexamer engages with FcR’s on multiple cell types and was engineered to maximize potency whilst minimizing
potential safety concerns. Initial in vitro and in vivo experiments showed differential efficacy for IgG1 and IgG4-hexamers and we used a statistical design approach (‘Design
of Experiments’) to explore the two extremes defined by these two isotypes.
15:35 Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency
Stylianos Bournazos, Ph.D., Research Assistant Professor, Molecular Genetics and Immunology, The Rockefeller University
A key immune evasion mechanism of HIV-1 is the low density of the envelope glycoprotein (Env) on the viral surface, which precludes high-avidity bivalent interactions of anti-Env antibodies. By engineering the hinge domain of IgG to favor heterobivalent
interactions, we generated bispecific anti-Env antibodies with improved neutralization potency and therapeutic activity. These findings suggest innovative strategies for generating engineered bispecific antibodies with enhanced activity, representing
ideal candidate molecules for HIV-1 and other viral infections.
16:05 Product Quality by Design: Cell Line Engineering to Enhance Specific FAP DR5 2+2 CrossMab Yields
Wolfgang Paul, Ph.D., Senior Scientist & Group Leader, Cell Culture Research Pharma Research and Early
Development, Large Molecule Research, Roche
The challenge for the production of new complex protein formats is the generation of cell lines producing high yields of functional proteins with low amounts of product related site products. The novel bispecific agonistic FAP-DR5 antibody contains
tetravalent binding properties (2+2 format), secreted with several product-related side products. The presented approach shows successfully the improvement of specific properties by subsequent transfection of a production cell line to decrease
the formation of these side products.
16:35 End of Conference
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