Cambridge Healthtech Institute’s 5th Annual

Novel Antibody Constructs and Alternative Scaffolds
Innovative Engineering, Novel Products, Unique Targets and Immune Modulation
5-6 November 2014

 

Speaker BiographiesDownload Brochure | Register 

In-depth research with the industry reveals the emergence of a wide range of exciting and innovative technologies with a variety of applications. In Europe there is a strong focus on platforms for bi-specific products, and on unique constructs and scaffolds, particularly on Fc engineering. This conference will present platforms for novel biotherapeutics with improved features such as enhanced access to the target site and better binding, and unique modes of action such as immune and complement activation. Presentations will cover target selection, and drug and platform discovery and development, and include challenges overcome and evidence for efficacy.

Recommended Short Courses*

SC1: Engineering of Bispecific Antibodies

SC2: Mutation and Selection Strategies for Multi-Parameter Antibody Optimisation

SC6: Troubleshooting and Engineering of Antibody Constructs

*Separate Registration Required.

Wednesday, 5 November

07:45 Registration and Morning Coffee


NOVEL APPLICATIONS OF BISPECIFIC TECHNOLOGY

08:30 Chairperson’s Opening Remarks

KatherineVousdenKatherine Vousden, Ph.D., Senior Scientist, Antibody Discovery and Protein Engineering, MedImmune






08:35 Seamless Transition from Mono- to Multi-Specific Antibodies Based on Light Chain Diversity

NicholasFischerNicolas Fischer, Ph.D., Head, Research, Novimmune SA

We have developed an antibody generation platform based on light chain diversity. Having at disposal antibodies sharing the same heavy chain enables the evaluation of antibody specificity in multiple formats and the scalable generation of bispecific antibodies as well as antibody mixtures. Due to their unmodified human IgG structure, the final products have characteristics that are identical to standard mAbs and are therefore ideally suited for development.

09:05 Engineering of Fully Human Bispecific Antibodies with Two Binding Sites in Each Fv Region

RolandBeckmannRoland Beckmann, Ph.D., Co-Founder and CSO, Dutalys

DutaMabs are fully human bispecific antibodies, comprising one normal heavy chain and one normal light chain, with two non-overlapping binding sites within the natural CDRs of each Fv. These two paratopes within the DutaMab CDRs are fully independent, due to an unprecedented stability, which exceeds that of all previously described antibodies. This allows the combination of any two specificities within one Fv, and their independent maturation to very high affinities.

09:35 A Novel Monovalent-Bispecific IgG Design

ParthaChowdhuryPartha S. Chowdhury, Ph.D., Principal Scientist, Antibody Discovery and Protein Engineering, MedImmune LLC

Most bispecific antibodies are multivalent in nature. For certain specific applications monovalent bispecific designs are better suited. A new design to generate monovalent bispecific IgGs will be described with a focus on biological and physic-chemical properties.

10:05 Biological Recognition: Beyond the Antibody

Ko_Ferrigno_PaulPaul Ko Ferrigno, Ph.D., CSO, Avacta Life Sciences

Antibodies are ubiquitous in life science research; their high affinity and specificity have enabled biological detection in a range of settings, from basic research to clinical diagnostics. Antibodies, however, are not suitable for all applications, and have limitations around targets and applications. Engineered non-antibody protein binders, largely focused on therapeutics, have been developed more recently. Here, I will review existing alternatives to antibodies and present Affimers as next generation reagents for biological recognition.

10:35 Coffee Break in the Exhibit Hall with Poster Viewing


Fc ENGINEERING APPROACHES

11:15 Antibody Engineering for Fc Silencing

TilmanSchlothauerTilman Schlothauer, Ph.D., Senior Scientist, Large Molecule Research, Pharma Research and Early Development, Roche Diagnostics GmbH

The constant part (Fc) of the human IgG interacts with various receptors of immune effector cells. The goal of our attempts was to establish the most silent antibody format without exerting any receptor-mediated effector functions e.g. for therapeutic use in inflammatory diseases. Several combinations of mutations have been tested in a comprehensive set of cell free and cell based in vitro functional tests, part of our Fc receptor platform.

11:45 Structural and Functional Insights into Neonatal Fc Receptor-Based Recycling Mechanisms

William_DallAcquaWilliam Dall’Acqua, Ph.D., Senior Director, Research and Development, Antibody Discovery and Protein Engineering-ADPE, MedImmune

We report the structure of the complex between human FcRn, human serum albumin (HSA) and a human Fc engineered for improved pharmacokinetic properties (Fc-YTE). A molecular explanation for HSA and IgG pH-dependent binding to FcRn is provided. We also explain structural mechanisms by which Fc mutations (including YTE) result in increased IgG binding to FcRn. Our study provides an unprecedented understanding of IgG and HSA interaction with FcRn.

12:15 ProxiMAX Randomisation: Non-Degenerate, Controllable Saturation Mutagenesis for Use in Antibody Engineering - Speaker Biography 

Anna HineAnna V. Hine, Ph.D., FSB, Reader, School of Life and Health Sciences, Aston University

‘ProxiMAX’ randomisation is a saturation mutagenesis process that encodes required chemical function without degeneracy. Either unbiased or pre-defined ratios of amino acids may be encoded and each saturated position can be defined independently. With achieved diversities of >99% (6 & 11 saturated codons) and the potential to generate libraries of up to 10^14 components, we contest that ProxiMAX randomization is key for engineering antibody libraries of the highest quality.

12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own


UNIQUE APPROACHES FOR CREATIVE ENGINEERING

14:00 Chairperson’s Remarks

NicholasFischerNicolas Fischer, Ph.D., Head, Research, Novimmune SA






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KEYNOTE PRESENTATION

14:05 Protein Inactivation in vivo in Intrabody-Expressing Mice

Stefan DübelStefan Dübel, Ph.D., Director, Biotechnology, Technische Universität Braunschweig

We demonstrate for the first time that endoplasmatic reticulum retained antibodies (“intrabodies”) can induce a knock down phenotype in transgenic mice. The phenotype found in adult mice expressing VCAM1 intrabodies included aberrant distribution of immature B-cells in blood and bone marrow. The availability of our technology and the rapidly growing number of available antibody genes will spark a new level for the functional study of membrane and plasma proteins in vivo.


14:35 Natural and Engineered Sortases for the Masses: A New Enabling Technology for Protein Engineers

ChristianFreundChristian Freund, Ph.D., Professor, Biochemistry, Freie Universitaet Berlin

Sortases, originating from the cell wall of gram-positive bacteria, can be used to ligate (poly) peptide-based scaffolds of various kinds. Their further development as ubiquitous tools hinges on the ability to modify their specificity and catalytic efficiency. We have recently created sortases with altered sorting motif specificity that indicate the potential of a newly developed sortase portfolio for traceless protein ligation.

15:05 Rationalising the Pharmacological Effect of a High Affinity Neutralizing Serpin Antibody through Co-Crystallography

KatherineVousdenKatherine Vousden, Ph.D., Senior Scientist, Antibody Discovery and Protein Engineering, MedImmune

Plasminogen activator inhibitor 1 (PAI-1) is an important mediator of fibrotic disease; understanding how antibodies neutralize this molecule is key for the development of therapeutics. We describe here the first co-crystal of PAI-1 with a high affinity neutralizing antibody. This has enabled the rationalization of in vivo and in vitro observations in the context of the resolved antibody epitope. How the isolation and affinity maturation strategy lead to the identification of this novel therapeutic will also be discussed.

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


INNOVATIVE ENGINEERING FOR DIFFICULT TO REACH TARGETS

16:15 Receptor-Mediated Delivery of a Bispecific Antibody into the Primate Brain: Challenges and Safety Findings

MarkDennisMark S. Dennis, Ph.D., Principal Scientist, Antibody Engineering, Genentech, Inc.

We have previously demonstrated that the transferrin receptor transcytosis pathway at the blood brain barrier (BBB) can deliver a therapeutically relevant dose of a bispecific antibody into the rodent brain. The therapeutic arm of the bispecific, directed against β-secretase (BACE1), significantly lowered brain A-beta production. This approach has now been extended to non-human primates. The challenges and safety findings encountered will be discussed.

16:45 Engineering Brain Shuttle Antibodies

JensNiewohnerJens Niewöhner, Ph.D., Principal Scientist, Large Molecule Research, Pharma Research and Early Development, Roche Diagnostics GmbH

By manipulating the binding mode of an antibody fragment to the transferrin receptor (TfR), we have developed a Brain Shuttle module, which can be engineered onto a standard therapeutic antibody for successful BBB transcytosis. The Brain Shuttle version of an anti-Abeta antibody, which uses a monovalent binding mode to the TfR, increases beta-Amyloid target engagement in a mouse model of Alzheimer’s disease, translating into a significant improvement in amyloid reduction.


17:15 Problem Solving Roundtable Discussions

Bispecific Protein Therapeutics

ParthaChowdhuryModerator: Partha S. Chowdhury, Ph.D., Principal Scientist, Antibody Discovery and Protein Engineering, MedImmune LLC

  • Bi-specific vs combo: Why and when?
  • Target pair identification and validation
    • Different formats and rationale
  • Key challenges and potential solutions
    • The next steps

Antibody Engineering - Chances and Challenges

RalfSchumacherModerator: Ralf Schumacher, Ph.D., Site Head, Large Molecule Research, Roche Penzberg & pRED

  • Integration of technological possibilities, MOA for targeted therapies, and disease understanding
  • Combination versus engineering, chances with eg targeting specific cells and organs
  • Challenges with complex Biologics facing the industry today
  • Integration of technical development and clinical development for complex Biologics

Targeting the Immune System

DavidUrechModerator: David Urech, Ph.D., CSO and Co-CEO, Numab AG





Engineering for Affinity and Specificity

KatherineVousdenModerator: Katherine Vousden, Ph.D., Senior Scientist, Antibody Discovery and Protein Engineering, MedImmune

  • Challenges of getting the balance right
  • Advantages at working this out at an early stage
  • Tools and technologies required
  • How this contributes to avoidance of formulation problems further down the line
  • Criteria for determining what goes forward
 

18:15 Networking Reception in the Exhibit Hall with Poster Viewing

19:15 End of Day One




Thursday, 6 November

08:00 Breakfast Presentation (Sponsorship Opportunity Available) or Morning Coffee


UNIQUE MODES OF ACTION

08:30 Chairperson’s Remarks

Stefan Dübel, Ph.D., Director, Biotechnology, Technische Universität, Braunschweig


KEYNOTE PRESENTATION

08:35 Philosophy and Principal Dogma behind Modern Discovery and Development of Biologics

Ralf SchumacherRalf Schumacher, Ph.D., Site Head, Large Molecule Research, Roche Penzberg & pRED

This talk will examine challenges facing the industry today, e.g. recognition of redundancy of pathways; the understanding of the signalling and interaction between cells and organs, e.g. what is responsible for suppression of the immune response to a cancer and how it can be overcome; the importance of linking together deep biological understanding, disease understanding, and MOA for targeted therapies, companion diagnostics for stratification of patients, and clinical study design. Examples will be provided.


09:05 Engineering of Probodies: Antibodies that Become Activated at the Target Site and Target Widely-Expressed Tumour-Specific Antigens

James West, Ph.D., Research Fellow, Protein Engineering, CytomX Therapeutics, Inc.

Antibodies have demonstrated therapeutic benefit through binding to targets in tumour tissues, however, engagement of targets also present in normal tissues can result in dose limiting toxicities. We have developed a novel antibody scaffold, the Probody, engineered to restrict antibody activity to the tumour. Probodies targeting EGFR or Jagged retain potent anti-tumour activity with substantially reduced on-target toxicities, demonstrating the power of the Probody platform to expand the target landscape to include widely expressed antigens for which conventional antibodies are not viable.

09:35 Novel Affitin Designs: Structural Basis for Two Modes of Action for Potent and Specific Inhibition of Glycosidases

FredericPecorariFrédéric Pecorari, Ph.D., Researcher, Cancer Research Center of Nantes-Angers, University of Nantes

Achieving specific and efficient inhibition of glycosidase enzymes is challenging as they can have similar mechanisms and active sites. We report two designs of artificial affinity proteins, Affitins, which specifically and potently inhibit two glycosidases. The crystal structures of glycosidase-Affitin complexes showed two binding modes, involving or not a loop, preventing substrate access to catalytic sites. The potential of Affitins to become general tailored enzymatic inhibitors will be discussed.

10:05 Sponsored Presentation (Opportunity Available)

10:35 Coffee Break in the Exhibit Hall with Poster Viewing


T CELL REDIRECTION AND IMMUNE MODULATION

11:15 Towards Predictability in Discovery and Engineering of Bispecific Therapeutics

DavidUrechDavid Urech, Ph.D., CSO and Co-CEO, Numab AG

The use of a single human variable domain scaffold allows for the reproducible engineering of highly stable and potent humanized rabbit antibody variable domains. Such variable domains are used as building blocks for the engineering of bispecific single-chain diabodies (scDb) with excellent CMC properties. Numab is exploiting bispecific scDbs with T killer cell redirecting activity for the therapy of chronic inflammatory diseases.

11:45 SM201/SM211: Two Anti-FcγRIIB mAbs Differing by a Single Amino Acid with Distinct Immunomodulatory Properties for the Treatment of Autoimmune Diseases

Peter SondermannPeter Sondermann, Ph.D., CSO, SuppreMol GmbH

FcγRIIB plays a central role in the negative regulation of the immune system. We describe two unique anti-FcγRIIB antibodies that recognize FcγRIIB but that do not interfere with the natural binding of the IγG-Fc part to the same receptor. The antibodies that differ just by a single amino acid recruit FcγRIIB to a different extent which renders them to be attractive drug candidates for the treatment of various autoimmune diseases.

12:15 End of Constructs and Scaffolds



Speaker BiographiesDownload Brochure | Register