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September 2018

Day One

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Wednesday September 27 2017

Registration & Networking

Chair’s Opening Remarks

Janine Schuurman, Vice President, Research, Genmab

Lessons Learned from the Clinical Development of Bispecifics

  • Investigating strategies to ensure the successful development of bispecifics in the context of unpredictable biologies and outcomes
  • Understanding how clinical experience can feed back and improve earlier development
  • Case study: overcoming unexpected immunogenicity of anti-TNF therapeutics – transferrable lessons to enhance your bispecific development

Tariq Ghayur, Senior Research Fellow, Abbvie

Engineering Bispecific Antibodies for Cancer therapy – a Unique Perspective for Pediatric Solid Tumors Spanning Three Decades

  • Contrasting how conventional IgG monoclonal antibodies (mAbs) relying on Fc-dependent mechanisms are constrained by low killing potency, poor cell trafficking, and inefficient epitope spread, whereas bispecific antibodies (BsAb) have the potential to turn circulating polyclonal T cells into tumor infiltrating cytotoxic T cells despite the immunosuppressive tumor microenvironment
  • Understanding how BsAb allows T-cell mediated immunotherapy to bypass the need for the expression of HLA and of costimulatory molecules on tumor targets, as well as prior immunization
  • Exploiting BsAb to deliver massive doses of radiation in multistep targeting with vastly improved therapeutic ratios

Nai-Kong Cheung, Head, Neuroblastoma Program, MSKCC

Model Aided Drug Invention Case Studies in Research: In silico Differentiation for Dual Targeting PD-1 and TIM-3 in I/O, and Predicting Optimal Drug Properties of a Bispecific Biologic to Maximize Tissue Targeting in OA

  • Quantitative Systems Pharmacology (QSP) is a mathematical modeling and engineering approach to translational medicine that aims to quantitatively integrate knowledge about therapeutics with an understanding of its mechanism of action in the context of human disease mechanisms
  • We will explore two case studies that highlight examples of QSP efforts that have de-risked projects, accelerated the discovery and development of best-in-class therapeutics, and impacted critical decisions, in the continuum from preclinical exploration to clinical research
  • First, we will look at an example of integrating systems modeling to predict optimal drug properties targeting PD-1 and TIM3 in immuno-oncology for bispecific biologics and fixed dose combinations
  • Second, we will look at QSP approaches to determine best in class properties for targeted anabolic growth factor to arthritic joints

John Burke, Co-founder, President & CEO , Applied BioMath

Speed Networking & Morning Refreshments

Discovery Track: Selecting & Validating Novel Targets Successfully

11.00 - OmniAb Platforms for the Generation of Fully Muman Mono and Bispecific Antibodies with Freedom-to-Operate

  • Investigating OmniRat and OmniMouse with human heavy and light chains diversity for monospecific antibodies
  • Understanding the advantages of OmniFlic rats with heavy chain diversity and a fixed common light chain for the development of bispecific antibodies
  • Analyzing immune response, sequence diversity, mono and bispecific antibodies generated from OmniFlic rats
  • Learning how OmniAb platforms are well validated by large number of partners; with multiple IND approvals and antibodies in clinical trials

Christel Iffland, VP, Antibody Technologies, Ligand Pharmaceuticals

11.30 - Information Content & Molecular Complexity: Importance of Library Design to Selection Results

  • Investigating how bispecific antibodies often require specific binding modes from their individual components to maximize potency and efficacy
  • Analyzing the effect of library design and size on the outcome of a selection for component of a tri-specific anti-HIV-1 entry inhibitors
  • Sharing insights into how large and carefully designed libraries can increase the probability of success when selecting for a molecule with specific functional features

Jonathan Davis, Principal Scientist, Protein Design, Bristol-Myers Squibb

12.00 - Optimization of Binding Strengths in a Tissue-Targeted Erythropoietin

  • Understanding how binding features of parent molecules may not be optimal in a bispecific.
  • Investigating how weak/moderate binding plus avidity can enhance specificity and how binding constants can affect both PK and signaling activity
  • We need a new roadmap for quantitative optimization of elements in multidomain engineered proteins.  We are working in a multidimensional landscape and need new design approaches beyond simply increasing throughput

Jeffrey Way, Senior Staff Scientist, Wyss Institute, Harvard University

Development Track: Laying the Foundations for Clinical Success Through Rational Early Development Strategies

11.00 - A New Mechanism of Action for Bispecific Antibodies Activating Tumor-Specific Antigen T Cells

  • Novel proprietary ex vivo assay for bispecific antibodies (BsAbs) in hematological malignancies patient samples
  • BsAbs can generate CTLs that kill tumor independent of BsAb and target, probably tumorspecific antigen CTLs immunosuppressed in bone marrow, same as TILs in solid tumors
  • New design of multi-specific antibodies from new MOA empowered by the screening of 100s of constructs ex vivo
  • Novel proprietary assay can screen combinations BsAbs and checkpoint inhibitors

Vivia Biotech

11.30 - Structural Optimization of Bispecific Antibodies for Conditional Immune Activation

  • Understanding how the formats make impact on mechanism of action
  • Controlling the toxicity of immune agonists by design
  • Learning to design better scFv as building blocks

Yoshiko Akamatsu, Senior Principal Research Scientist, Abbvie

12.00 - The Use of Pharmacodynamic Biomarkers to Understand Mechanisms of Bispecific Redirected T-cell Therapies in Preclinical Tumor Models

  • Developing bispecific therapeutics which engage and activate endogenous polyclonal T cell populations via the CD3 complex in solid tumors expressing target antigens
  • Characterizing the mechanisms of efficacy and resistance of these CD3 bispecifics using pharmacodynamic assays including morphometric assessments
  • These data may be used to guide potential combination strategies for redirected T cell therapies

Andrea Hooper, Senior Principal Scientist, Targeted Therapeutics Discovery, Pfizer

Lunch & Networking

Investigating & Contrasting Innovative Bispecific Constructs

Avoiding Pitfalls in Format Design – Understanding Why Bispecifics Have Behaved Unexpectedly in the Past to Give a Greater Certainty in Moving into the Clinic in the Future

  • Analysing the advantages and disadvantages of a variety of bispecific formats
  • Performing a reality check on the hype surrounding bispecifics – addressing the need to improve potency, control immunogenicity risk and enhance developability
  • Key lessons learned from the development and advancement of therapeutic bispecifics in oncology

Dale Ludwig, CSO, Biologics Technology, Oncology Research, Eli Lilly

Making Room for Two Paratopes on an Fv: Introducing the DutaFab Platform

  • The DutaFab platform delivers fully human dual targeting Fab molecules with two independent paratopes
  • Heavy and light chain both contribute to high affinity target binding for each of the paratopes
  • Binders can be mixed and matched and reformatted into antibody formats as desired
  • This creates novel bispecifics structurally essentially indistinguishable from a standard monospecific Fab or antibody
  • We introduce the platform technology and discuss applications

Marlon Hinner, Group Leader, In Vitro Display, Roche

Panel Discussion: Investigating Comparisons Between Formats – Lessons Learned that will Inform Future Format Design

  • Head to head comparisons investigating why certain arrangements of domains are more efficacious than others in addressing the same targets
  • Investigating how in vitro performance compares to in vivo performance for the different formats currently available
  • Understanding which formats and approaches can successfully meet the criteria required for manufacturability

Robert Mabry, Senior Director, Protein Sciences & Antibody Technology, Jounce

Stan Blein, Senior Director & Head, Antibody Engineering Innovation & Development, Glenmark

Marlon Hinner, Group Leader, In Vitro Display, Roche

Afternoon Refreshments & Networking

Improving the Developability of Bispecifics

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

  • Single cell process simplifies bispecific antibody production compared to established assembly process from two component antibodies
  • Molecular insights into how engineered Fab domains drive orthogonal pairing of cognate light and heavy chains
  • More complex characterization of single cell bispecific antibody overcome with high resolution analytics
  • Single cell process translates to stable cell line development, a key step for clinical development

Christoph Spiess, Senior Scientist, Antibody Engineering, Genentech

Site-Specific Bioconjugation Approaches for the Preparation of Novel Bispecific Antibody Platforms

  • Chemical crosslinking techniques can be used to rapidly prepare highly uniform bispecific antibody constructs, opening up an opportunity to screen for optimal antigen binding pairs
  • Proximity-based sortase ligation can be used to site-specifically modify bispecific antibodies with chemical moieties (e.g. imaging agents, PEG) in a modular fashion, during standard protein purification protocols

Andrew Tsourkas, Professor, Bioengineering, University of Pennsylvania

Developability & Analytical Characterization to Enable the Optimal Selection of Bispecific Antibodies

  • Analytical characterization of developability attributes of bispecific antibodies during discovery
  • Selection of highly developable lead molecules with minimum downstream issues
  • Key learning for bispecific antibody production, purification, and characterization

Laurence Fayadat-Dilman, Director, Protein Sciences, Merck

Chair’s Closing Remarks

Janine Schuurman, Vice President, Research, Genmab