PEGS_2015_Track-Banner_Engineering-Bispecific


This conference will highlight different approaches to bispecific antibody constructs and reveal key elements for efficacy and drug-like properties. Disease areas beyond oncology will be reviewed, such as ophthalmology, infectious disease, and inflammatory diseases. Aspects for enhancement such as purification, stability, neutralization, enhanced targeting, modulating immune response, expression, characterization, improvements in humanization and clearance will be considered.

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Recommended Pre-Conference Short Courses* 

SC1: Phage and Yeast Display Libraries  

SC5: Troubleshooting and Engineering of Antibody Constructs 

*Separate registration required.

THURSDAY, MAY 7

 

Creating the Next Wave of Bispecifics  

12:00 pm Registration

12:35 Luncheon in the Exhibit Hall with Poster Viewing

1:40 Chairperson’s Remarks

Robert Mabry, Ph.D., Director, Protein Sciences and Antibody Technology, Jounce Therapeutics

1:50 KEYNOTE PRESENTATION

Teaching Antibodies New Tricks: From Simulation to Clinical Benefit of Bispecific Antibodies

Ulrich B. Nielsen, Ph.D., Chief Scientific Officer & Senior Vice President, Merrimack

Bispecific antibodies offer the potential to create highly specific therapeutics, with greater potency and even have the ability to inhibit multiple targets. This makes the therapeutic design process extremely complex because specificity, affinity and valency all need to be optimized in parallel. In our design process, we employ computational network models to engineer bispecific antibodies that embrace these complexities and address issues of tumor cell heterogeneity and network redundancies. We will present examples from three of Merrimack’s bispecific antibodies that are currently in development.

2:20 Discovery, Characterization & Optimization of Bispecific Antibodies by Developing Structure/Activity Relationships Using an Engineered Cell-Free Expression System

Trevor J. Hallam, Ph.D., Chief Scientific Officer, R&D, Sutro Biopharma, Inc.

Rapid transition of bispecific antibody candidates from initial discovery to development is enabled by selection of scFvs and Fabs from highly diverse libraries expressed using cell-free synthesis. Empirical selection of antigen-binding combinations enables selection of bispecific candidates that can be rapidly expressed for high-throughput characterization. Scaling to multiple gram quantities to support pharmacology and toxicological assessments can then be achieved within days.

2:50 Structurally Motivated Approach to Design Bispecific Antibodies with Improved Developability Properties

Srinath Kasturirangan, Ph.D., Scientist I, Antibody Discovery and Protein Engineering, MedImmune Inc.

While current scFv-based BiSAbs offer a variety of geometries between antigen binding sites, some spacing options are lacking. Using a structurally-motivated approach we designed additional variants with scFvs inserted into surface-exposed loops of an IgG1 Fc. The scFvs in these BiSAb variants are N- and C-terminally constrained, potentially preventing domain exchange and aggregate formation, thereby precluding the need for scFv engineering to stabilize the molecule.

3:20 High-Throughput Design, Production, and Evaluation of Bispecific Antibodies

Maria Wendt, Ph.D., Senior Scientific Consultant, Biologics, Genedata

Work on multispecific antibodies has exploded and more sophisticated engineering approaches are now used. Concurrently, increasing numbers of bispecific platforms (e.g. tandem-scFv-Fc, DVD-Ig, diabodies, KiH) and parametric variants (e.g. linkers, V-domain orientation, Fc) must be tested in higher throughputs. We present the latest advances in our workflow platform for in-format screening, fully automated molecule design, DNA synthesis and verification, and platform-specific expression processes (e.g. post-production exchange reactions). Integrated into a comprehensive data management system for samples, assays, and analytics results, the platform enables systematic evaluation of large panels of next-generation antibodies.

3:50 Refreshment Break

 

APPLICATIONS IN INFECTIOUS DISEASE 

4:15 Chairperson’s Remarks

G. Jonah Rainey, Ph.D., Senior Scientist, ADPE, MedImmune, LLC

4:20 Back to the Future: From Serum Therapy to Infectious Disease Monoclonal Antibodies

Eszter Nagy, M.D., Ph.D., Co-Founder, President and CSO, Arsanis, Inc; Managing Director, Arsanis Biosciences GmbH

The emergence of antibiotic resistance and the inability of antibiotics to counteract bacterial toxins implicated in severe bacterial infections call for novel approaches. Monoclonal antibody therapeutics are proven to be highly efficacious in many disease areas but rarely considered as anti-infectives. The complex pathogenesis of bacterial infections is considered as a formidable barrier for anti-bacterial antibody therapeutics. Therefore, multi-specific binding characteristics and cocktails of mAbs need to be considered.

4:50 Engineering Fully Human Anti-Infective Antibodies for Dengue Therapy

Paul MacAry, Ph.D., Associate Professor, Microbiology, National University of Singapore

In my talk, I will outline how we apply advanced antibody engineering approaches to make fully-human, therapeutic antibody candidates for acute viral infection with an emphasis on Dengue virus. I will also outline the thorough characterization of these antibodies and discuss the implications that these data have for our understanding of natural immunity plus future therapy for Dengue.

5:20 End of Day

5:15 Registration for Dinner Short Courses

 

Recommended Dinner Short Course* 

SC10: Next-Generation Sequencing of Antibody Libraries: Bridging Experimental and Bioinformatic Methods  

*Separate registration required.

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FRIDAY, MAY 8

8:00 am Morning Coffee

 

DELIVERY ACROSS THE BLOOD-BRAIN BARRIER 

8:30 Chairperson’s Remarks

Eric Smith, Ph.D., Associate Director, Bispecifics, Regeneron Pharmaceuticals

8:35 Engineering Blood-Brain Barrier-Crossing Bispecific Biologics

Unpublished DataGraham K. Farrington, Ph.D., Director, Chemical & Molecular Therapeutics, Antibody Discovery, Biogen Corporation

The blood-brain barrier (BBB) serves to limit access of antibodies to the brain parenchymal space. There has been much effort by various groups to engineer antibodies that use receptor mediated transcytosis to enhance serum to parenchymal antibody transport and thereby increase parenchymal antibody concentration. This presentation will focus on engineering proteins to maximize cross BBB transport. The effects of mono- and bidentate molecules on cross BBB transport, the triage of molecules across a series of in vitro and in vivo assays and considerations around Fc functionality to select for the most effective transport molecule will be discussed.

9:05 Receptor-Mediated Delivery of a Bispecific Antibody into the Primate Brain: Challenges and Safety Findings

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

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

9:35 Functional Characterization of Blood-Brain Barrier-Crossing Antibodies

Unpublished DataDanica B. Stanimirovic, M.D., Ph.D., Director, R&D, Translational Bioscience, Human Health Therapeutics Portfolio, National Research Council of Canada

The talk will cover workflows for functional characterization of engineered blood-brain barrier-crossing bi-specific biologics spanning in vitro and in vivo models. With recent advances in the development of molecular Trojan horses for brain delivery of large molecules, humanized in vitro BBB models and in vivo assessment allowing better PK/PD modeling, correlative and scale-up studies, will become critical to ensure clinical translation of CNS-targeting biologics.

10:05 Coffee Break

 

NEW METHODS FOR GENERATING BISPECIFIC ANTIBODIES: What Unique Properties Do They Have for Solving Problems? 

10:30 Chairperson’s Remarks

Martin Steegmaier, Ph.D., MBA, Head of Discovery, Large Molecule Research, Pharma Research & Early Development, Roche Innovation Center Penzberg

10:35 FIT-Ig: A Novel Bispecific Antibody Format Combining Any Two mAbs into One Bi-Functional Ig Molecule

Unpublished DataRobert Kamen, Ph.D., Epimab Biotherapeutics

FIT-Ig is a new bispecific antibody format providing Ig-like, tetravalent, bispecific molecules with a standard Fc region. The heavy and light chains of FIT-Ig’s are co-expressed in mammalian cells and secreted at high levels as single protein species, which can be readily purified. FIT-Ig’s retain the full biological functions of the two parental mAbs, exhibit antibody-like pharmacokinetics as well as overall protein stability and solubility. This highly versatile bispecific design shows promise for next generation biotherapeutics.

11:05 Designing and Discovering Transformative Bispecific Antibody Therapeutics

Martin Steegmaier, Ph.D., MBA, Head of Discovery, Large Molecule Research, Pharma Research & Early Development, Roche Innovation Center Penzberg

The range of therapeutic uses for bispecific antibodies is expanding beyond oncology. This presentation will show the state of the art in bispecific heterodimeric IgG antibodies, with an emphasis on recent progress using CrossMAb technology to generate bispecific antibodies by IgG domain exchange. Examples given will include new bispecific molecules for ophthalmology indications and the use of Roche’s Brain Shuttle technology to treat neurological disorders.

Unpublished Data11:35 Bispecific Fynomabs: Novel Mode-of-Action through Tailored Architecture

Simon Brack, Ph.D., Director, Discovery Research, Covagen AG

We will present data to illustrate how FynomAbs with tailored architecture are generated to overcome limitations encountered with other therapeutic protein formats. As an example, we will present CD3 bispecific FynomAbs with strong anti-tumor activity but with virtually no toxicity on normal tissues expressing low but detectable levels of target antigen.

12:05 pm Facile Generation of Common Light Chain Bispecific Antibodies

Unpublished Data and Case StudyEric M. Krauland, Ph.D., Senior Director, Antibody Discovery and Optimization, Adimab LLC

A variety of bispecific constructs benefit from the use of a single variable light region pairing with multiple distinct variable heavy regions. This talk will demonstrate the facile engineering of multiple VHs that pair with a single light chain. A panel of bispecific constructs are then generated that bind to each target with high affinity and exhibit favorable biophysical properties similar to traditional therapeutic antibodies.

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:05 Refreshment Break

1:35 Chairperson’s Remarks

Martin Steegmaier, Ph.D., MBA, Head of Discovery, Large Molecule Research, Pharma Research & Early Development, Roche Innovation Center Penzberg

1:40 Bispecific Antibodies against HIV-1 and Cancer-Related Proteins

Dimiter S. Dimitrov, Ph.D., Senior Investigator, Experimental Immunology Laboratory, National Cancer Institute, NIH

We have designed, generated and characterized novel exceptionally potent bispecific fusion proteins of engineered antibody domains targeting the HIV-1 co-receptor binding site and one domain soluble CD4. They inhibited entry of all tested (more than 100) isolates in vitro and exhibited high potency in an animal model of HIV-1 infection. We have also developed bispecific antibodies targeting non-overlapping domains on IGF2. They form multimolecular complexes which through avidity effects bind to CD16a expressing cells much stronger than monomolecular antibodies and could lead to irreversible removal of IGF2 from the circulation.

2:10 IMCgp100 ImmTAC: A Bispecific TCR Anti-CD3 Fusion for the Treatment of Malignant Melanoma

Annelise Vuidepot, Ph.D., Head, Protein Science, Immunocore Ltd.

ImmTACs are soluble bispecific-TCR-antiCD3 fusions suitable for the treatment of several tumor types. Unlike antibodies, TCRs target MHC-bound peptide antigens derived from endogenously processed proteins, providing a large pool of intracellular antigens from which to select appropriate target molecules. Our most advanced program, IMCgp100, is currently in a phase IIa clinical trial for the treatment of malignant melanoma.

2:40 Optimization and Application of an Fc-Containing Bispecific Platform

John R. Desjarlais, Ph.D., Chief Scientific Officer, Xencor, Inc.

Xencor has developed a novel bispecific platform that incorporates an antibody Fc domain in order to promote antibody-like half-life and convenient dosing. I will discuss optimization of the platform and its application to several therapeutic programs.

3:10 The Nanobody Platform: Opportunity for Next-Generation
Multispecific Protein Therapeutics

Unpublished DataCatelijne Stortelers, Ph.D., Senior Scientist and Technology Project Leader, Discovery, Ablynx

Nanobodies are clinically validated protein therapeutics based on the smallest functional fragments of naturally-occurring heavy-chain only antibodies. Ablynx has generated functional Nanobodies across a wide range of target classes enabling straight-forward multimeric drug targeting across several formats. The Nanobody platform provides excellent formatting flexibility allowing full control and tuning over valency, avidity and specificity. In combination with the excellent manufacturing and biophysical properties, Nanobodies are the ideal targeting agents for next-generation protein therapeutics. This will be exemplified by several of our drug pipeline candidates in clinical and preclinical development.

3:40 Bispecific Antibodies Targeting Tumor Antigens and Complement Regulators Increase The Efficacy of Antibody-Based Immunotherapy

Paolo Macor, Ph.D., Life Sciences, University of Trieste

The efficacy of antibody-based immunotherapy is often due to the activation of complement-dependent cytotoxicity but very few studies tried to enhance complement-mediated functions. We now report the generation of two bispecific antibodies that were designed to recognize tumor-associated antigens and to neutralize complement regulatory proteins, over-expressed on tumor cell surface. The bispecific antibodies targeting CD20 on B-lymphoma cells prevents tumor development and results in the survival of all tumor-bearing animals.

4:10 End of Conference

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