Cambridge Healthtech Institute’s Inaugural

Bispecific Antibody Design

Successful Strategies

August 20 - 21, 2018


Bispecific antibodies continue to show significant and impressive therapeutic value. While the development of bispecific antibodies is an evolving field, many challenges are still waiting to be solved by experts in the field, including target selection, heterodimerization, understanding of their mechanism of action, along with developability assessment and manufacturing concerns. CHI’s Bispecific Antibody Design conference will delve directly into the technical challenges of bispecific development to improve your candidates’ translatability into the clinic.

Final Agenda

MONDAY, AUGUST 20

12:00 pm Conference Registration

DUAL TARGETING, TARGET SELECTION AND ENGAGEMENT

1:30 Chairperson’s Opening Remarks

Roland E. Kontermann, PhD, Professor, Institute of Cell Biology and Immunology, Stuttgart Research Center Systems Biology, University of Stuttgart

 

1:40 KEYNOTE PRESENTATION: Future Prospects for Bispecific Antibody Development

Janice_ReichertJanice M. Reichert, PhD, Executive Director, The Antibody Society

Bispecific antibodies hold substantial potential for treatment of numerous human diseases. Nearly 70 bispecific antibodies are currently in clinical studies, with approximately 2/3 of these entering studies in the past 3 years. These molecules are thus of substantial interest to the biopharmaceutical industry, but only limited efficacy data is available because few have completed late-stage clinical studies. Dr. Reichert will discuss the bispecific antibody pipeline and future prospects for their approval.

View a recent interview with Janice Reichert

2:10 Novel Multispecific Therapeutic Platform Design

Stephen_DemarestStephen J. Demarest, PhD, Senior Research Fellow, Protein and Antibody Engineering, Lilly Research Labs

Over the past several years, we have generated several structure-based designs to control both antibody heavy chain/heavy chain and heavy chain/light chain pairing. In the presentation, I will describe how these designs can be used to co-express multiple Fabs simultaneously to generate correctly assembled multispecifics of varied design and activity.

2:40 Unbiased Functional Screening of Large Bispecific Antibody Panels to Unlock Novel Biology

Mark_ThrosbyMark Throsby, PhD, CSO, Merus NV

The bispecific antibody format represents an emerging therapeutic modality. We have developed a set of robust and validated technologies that permits unbiased in-format functional screening to identify human full-length IgG bispecific antibodies candidates with superior therapeutic properties. Two case studies will be presented where this approach has been successfully employed to discover lead candidates with differentiating properties that are now in clinical development.

3:10 Networking Coffee Break

3:40 DuoBody Technology: A Versatile Platform for Bispecific Antibody Discovery and Development

Rick_HibbertRick Hibbert, MBA, PhD, Assistant Director, Protein Production & Chemistry, Genmab B.V.

The DuoBody® platform represents a versatile, elegant and robust technology for generating bispecific antibodies. The post-production process is based on controlled Fab-arm exchange and yields bispecific antibodies that retain the molecular structure and quality attributes of therapeutic IgGs. The process is robust, high-throughput compatible and shows linear scalability from bench to manufacturing scale. This presentation will highlight recent insights in the developability and analytical characterization of DuoBody products.

4:10 The Era of T Cell Bispecific Cancer Immunotherapy: Insights for Bioassay Strategies for Bispecific Molecules

Ho_Young_LeeHo-Young Lee, PhD, Senior Scientist, Biological Technologies, Genentech

T cell bispecific molecules are a novel class of immunotherapy, and the number of programs in clinical trials has increased dramatically in recent years. We will present bioassay strategies and data, which can cover various CD3-bispecific molecules as platform methods, and provide insights into the efficacy of bispecific products and the safety of unique impurities.

4:40 FEATURED PRESENTATION: A Regulator’s Perspective on Trends and Challenges in the Development Bispecific Antibodies

Marjorie_ShapiroMarjorie A. Shapiro, PhD, Supervisory Biologist, Office of Biotechnology Products/CDER/FDA

Monoclonal antibodies are the most successful class of biological products, with an increasing number of approvals in recent years, including two bispecific antibodies (BsAb). BsAbs are also an increasing proportion of the antibody-related products entering clinical development. The complexity of these constructs adds additional development, manufacturing analytical and regulatory challenges for sponsors and regulators. This presentation will describe FDA’s experience with BsAbs.

5:10 Welcome Reception in the Exhibit Hall with Poster Viewing

6:10 End of Day

TUESDAY, AUGUST 21

8:00 am Registration and Morning Coffee

ENGINEERING INNOVATIONS FOR BISPECIFICS

8:30 Chairperson’s Remarks

Rick Hibbert, MBA, PhD, Assistant Director, Protein Production & Chemistry, Genmab B.V.

8:35 KEYNOTE PRESENTATION: Preclinical and Clinical Lessons from the DVD-Ig Platform

Tariq_GhayurTariq Ghayur, PhD, Distinguished Research Fellow, Immunology Discovery, AbbVie

Several bispecific DVD-Ig molecules have now been tested in preclinical models and in clinic. The emerging data show that these molecules behave like monoclonal antibodies and that the DVD-Ig format per se is not immunogenic. However, target biology may play an important role in anti-drug antibody response (ADA, immunogenicity). Lessons learned from these studies will be discussed.

9:05 Bivalent and Tetravalent Bispecific Antibodies for Cancer Therapy

roland-kontermannRoland E. Kontermann, PhD, Professor, Institute of Cell Biology and Immunology, Stuttgart Research Center Systems Biology, University of Stuttgart

Dual targeting of two receptors, e.g. of the EGFR receptor family, holds great promise to increase efficacy and to overcome resistance by compensatory receptor signaling. Data will be presented of various bispecific antibody formats, being either bivalent or tetravalent, for efficient inhibition of two receptors, comprising a novel neutralizing anti-HER3 antibody recognizing a unique epitope combined with antibodies against other members of the EGFR receptor family.

9:35 Development of T Cell Dependent Bispecifics for Heme Malignancies

Meric_OvacikMeric Ovacik, PhD, Scientist, Preclinical Translational Pharmacokinetics, Development Sciences, Genentech

Bispecific IgG production in single host cells has been a much sought-after goal to support the clinical development of these complex molecules. This talk will focus on novel designs to facilitate selective Fab arm assembly in conjunction with previously described knobs-into-holes mutations for preferential heavy chain heterodimerization. The single-cell bispecific IgG designs developed here may be broadly applicable to biotechnology research, including screening bispecific IgG panels, and to support clinical development.

10:05 Development of A Novel Bispecific Immune Modulating Antibody

NEW SPEAKER: Tibor Keler, PhD, CSO, Celldex Therapeutics, Inc.

The success of antibodies that block the PD-1 signaling pathway has led to a tremendous effort in combination therapy to further improve outcome in responsive cancers and to overcome resistance. CD27 is a costimulatory molecule that provides a complementary target to the PD-1/PD-L1 axis on T cells. Here we report the preclinical results of our development-stage program targeting CD27 and PD-L1 as a bispecific antibody. A simple tetravalent format was selected that allows very efficient cross-linking, which is important for CD27 agonistic activity, by providing the opportunity to interact with both Fc receptor and PD-L1 bearing cells. Celldex also has antibodies in our discovery and clinical pipelines targeting additional points of intervention of the cancer-immunity cycle that are being explored in similar bispecific approaches.

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

DEVELOPABILITY ASSESSMENT AND MANUFACTURING

11:15 Chairperson’s Remarks

Mark Throsby, PhD, CSO, Merus NV

 

11:20 Bispecific Platform Designed for Rapid Development and Manufacturing of Novel Protein Therapeutics

Peter_PavlikPeter Pavlik, PhD, Principle Scientist, Aptevo Therapeutics

This talk will cover a comprehensive overview of Aptevo’s next generation ADAPTIRTM platform, highlighting improvements that have led to the development of new ADAPTIRTM candidates with increased stability, superior manufacturability and antibody expression levels, and an extended half-life of up to 12.5 days in rodents.

 

11:50 Discovery, Optimization, and Developabilty Profiling of Common Light Chain CD3 Bispecifics

Robert_PejchalPaul Widboom, PhD, Associate Director, Antibody Discovery, Adimab LLC

Common light chain (LC) bispecific antibodies represent a native-like format that both simplifies production and solves the LC pairing problem without introduction of mutations into constant regions of the Fab. Adimab’s discovery and optimization platform was used to generate CD33 and HER2 antibodies utilizing a CD3 LC. Bispecifics binding to HER and CD3 were produced and characterized for affinity, developability, and functional activity. Approaches for tuning CD3 affinity in a common LC setting are also highlighted.

12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

IMAGING AND THERANOSTIC APPLICATION OF BISPECIFICS

2:05 Curative Anti-DOTA IgG-scFv Bispecific Antibody Pretargeted Radioimmunotherapy (DOTA-PRIT) of Colorectal Cancer Monitored by Quantitative SPECT/CT-Based Theranostics

Sarah_ChealSarah Cheal, PhD, Senior Research Scientist, Memorial Sloan Kettering Cancer Center

The therapeutic indices (TIs) of antibody-targeted radionuclide therapy are often insufficient for effective treatment of solid tumors. To overcome this, we utilize a novel 3-step pretargeted radioimmunotherapy (PRIT) strategy based on a glycoprotein A33 (GPA33)-targeting bispecific antibody and a small-molecule radioactive DOTA hapten, a complex of 177Lu and S-2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (177Lu-DOTA-Bn) to achieve high TIs for radiosensitive tissues such as blood (TI = 73) and kidney (TI = 12). We show that a fractionated anti-GPA33 DOTA-PRIT regimen calibrated to deliver a radiation absorbed dose to tumor of more than 100 Gy leads to a high probability of tumor cure while being well tolerated by nude mice bearing subcutaneous GPA33-positive SW1222 xenografts.

2:35 Dual-Targeted Molecular Imaging of Cancer

Emily B. EhlerdingEmily B. Ehlerding, MS, Medical Physics, University of Wisconsin - Madison

Molecular imaging techniques using bispecific agents hold great potential to increase our imaging capabilities. We will herein discuss several positron emission tomography (PET) studies that have been accomplished using bispecifics, pointing out the benefits of using such platforms for imaging, and outlining directions for future research in this field. 

3:05 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Problem Solving Roundtable Discussions

These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are below. Please click here for full details on all breakouts.

The Design and Therapeutic Application of Bispecific Antibodies

Moderator: Stephen J. Demarest, PhD, Senior Research Fellow, Protein and Antibody Engineering, Lilly Research Labs

  • The use of antibody combinations versus bispecific antibodies: Pros and Cons discussions
  • What are developability challenges of the most common bispecific antibody platforms?
  • Future areas of design / engineering to enable improved bispecifics
  • Given the vast amount of research into bispecifics, why have more not crossed the finish line?

The Selection and Development of Bi-Specific Antibodies with “Novel” Biology (1 + 1 = > 2)

Moderator: Tariq Ghayur, PhD, Distinguished Research Fellow, Foundational Immunology, AbbVie

  • Examples of bi-specific antibodies with novel biology
  • Potential HTP cell-based functional screens to identify bi-specific antibodies with novel biology
  • Optimization of the bi-specific format to achieve desired functional outcomes.
  • How to assess translational issues related to novel biology?

4:45 End of Bispecific Antibody Design