The field of bispecific antibodies is advancing rapidly with results demonstrating their effective use in immunotherapy and oncology, as well as applications that are emerging in ophthalmology, infectious disease, and inflammation. This conference will highlight novel engineering approaches to bispecific antibody constructs and reveal key elements for efficacy and drug-like properties. The latest improvements in manufacturing, purification, stability, enhanced targeting, modulating immune response, expression, characterization, humanization and clearance will be shared.
Scientific Advisory Board
Christian Klein, Ph.D., Discovery Oncology oDTA, Pharma Research and Early Development (pRED), Roche Glycart AG
Robert Mabry, Ph.D., Director, Protein Sciences and Antibody Technology, Jounce Therapeutics
G. Jonah Rainey, Ph.D., Senior Scientist, ADPE, MedImmune, LLC
Eric Smith, Ph.D., Associate Director, Bispecifics, Regeneron Pharmaceuticals
THURSDAY, APRIL 28
12:35 pm Luncheon in the Exhibit Hall with Poster Viewing
1:40 Chairperson’s Remarks
G. Jonah Rainey, Ph.D., Senior Scientist, ADPE, MedImmune, LLC
1:50 KEYNOTE PRESENTATION:
Ang-2/VEGF Bispecific Antibody Reprograms Macrophages and Resident Microglia to Anti-Tumor Phenotype and Prolongs Glioblastoma Survival
Dai Fukumura, M.D., Ph.D., Deputy Director, Edwin L. Steele Laboratory; Biologist, Department of Radiation Oncology, Massachusetts General Hospital; Associate Professor, Harvard Medical School
2:20 CrossMAb Vh-Vl and Fab
Jörg T. Regula, Ph.D., Head, Protein Analytics, Roche Diagnostics GmbH
The CrossMAb technology (Schäfer et al., 2011) can be used to generate a bispecific antibody from two independent parental antibodies by immunoglobulin domain exchange. The three different CrossMAb designs were named according to their exchanged domains: CH1-CL, Vh-Vl and Fab. The CrossMAb CH1-CL was used for the Ang2-VEGF CrossMAb (Kienast et al. 2013). The introduction of additional modifications renders the CrossMAb Vh-Vl and the CrossMAb Fab to suitable alternatives. The CrossMAb technology enables several bispecific molecules with 1+1, 2+1 or 2+2 binding sites.
2:50 Multimerization Strategy to Enhance Potency and Developability of Bispecific Antibodies
Mahiuddin Ahmed, Ph.D., Assistant Attending for Immunotherapies, Pediatrics, Memorial Sloan Kettering Cancer Center
Bispecific antibodies have proven to be highly efficient at re-directing T cells for cancer immunotherapy. In order to enhance the anti-tumor potency and developability of tandem scFv bispecific antibodies (tsc-BsAbs or BITEs), we exploited the dimerization domain of the human transcription factor HNF1α to enhance the avidity of a tsc-BsAb to the tumor antigen disialoganglioside GD2 while maintaining functional monovalency to CD3 to limit potential toxicity.
3:20 Engineering Next-Generation Biotherapeutics: Developability & Manufacturability
Maria Wendt, Ph.D., Head , Science, Genedata
Next-gen biotherapeutics, specifically bi- and multi-specifics, alternative scaffolds and ADCs, provide significant advantages over traditional IgG-based molecules. As highly engineered molecules, they pose new design, cloning, expression, purification and analytics challenges. Our workflow platform automates the engineering, production, and testing of large panels of candidate therapeutic molecules. We demonstrate its capability to explore the huge combinatorial space of novel molecule-specific designs as well as its high-throughput capability and built-in tools for assessing developability and manufacturability.
3:50 Refreshment Break
4:20 Bispecific FynomAbs with Tailored Architecture and Novel Modes-of-Action
Simon Brack, Ph.D., Director, Discovery Research, Covagen (one of the Janssen pharmaceutical companies of Johnson & Johnson)
Covagen develops bispecific FynomAbs by fusing its human Fynomer binding protein to antibodies, resulting in bispecific protein therapeutics with novel modes-of-action and enhanced efficacy for the treatment of inflammatory diseases and cancer. We will present case studies demonstrating that FynomAbs with tailored architecture overcome limitations encountered with other therapeutic protein formats, such as suboptimal efficacy or lack of tumor selectivity.
4:50 How to Minimalize Antibodies: The Success of Antibodies as Pharmaceuticals has Triggered Interest in Crafting Much Smaller Mimics
Patrick J. McEnaney, Ph.D., Postdoctoral Researcher, Departments of Cancer Biology and Chemistry, The Scripps Research Institute Florida
In the past decade monoclonal antibodies have revolutionized the treatment of cancer. These antibodies possess excellent specificity and affinity for cell targets, and can perform their function through hijacking of native immune effector functions. However, the potential drawbacks are daunting, including immunogenicity, issues with scalability, storage and cost. This talk will look to leverage the specificity and efficacy seen with large biological agents through utilization of modular synthetic constructs, showing the development and optimization of a fully synthetic molecule capable of eliciting a targeted, specific immune response against prostate cancer.
5:20 End of Day
5:15 Registration for Dinner Short Courses*
FRIDAY, APRIL 29
8:00 am Registration and Morning Coffee
8:30 Chairperson’s Remarks
Robert Mabry, Ph.D., Director, Protein Sciences and Antibody Technology, Jounce Therapeutics
8:35 Arming of Effector T Cells with Bispecific Antibodies or Chimeric Antigen Receptors
Armin Ehninger, Ph.D., Chief Scientific Officer, GEMoaB Monoclonals GmbH
In parallel to conventional single-chain bispecific antibodies and chimeric antigen receptors we have established a modular platform technology (UniTARG) for retargeting of T cells with complexes in either a bispecific antibody (UniMAB) or a chimeric antigen receptor (UniCAR) format for simultaneous or subsequent application against different antigens, and, if desired, co-delivery of co-stimulatory or inhibitory signals. This innovative technology enables a highly accelerated and flexible development of efficient tumor therapies.
9:05 Developing Full-Length CD3 Bispecific Antibodies: From Bench to NHP
Javier Chaparro-Riggers, Ph.D., Director, Antibody Technology, Rinat Pfizer, Inc.
The T cell engaging antibody Blinatumumab against CD19 has been approved recently, but the short half-life makes continuous infusions necessary. We implemented a full-length IgG T cell engaging platform, which increases the half-life and allows conventional dosing. Optimization of the platform from bench to NHP will be presented.
9:35 (scFab)2-Fc Type Bispecific Antibodies Engaging T Cells for Cancer Immunotherapy
Hyung-Kwon Lim, Ph.D., Senior Research Scientist, Antibody Engineering, MOGAM Biotechnology Institute
This presentation will describe a recent work for the (scFab)2-Fc format bispecific antibodies and its applications toward T cell engagement for cancer immunotherapy. Using this platform, several bi-specific antibodies targeting T cell and tumor specific antigens were constructed. The challenges and opportunities of this format in terms of heterodimerization yield between two heavy chains, any modifications of Fc functions and mass analyses will be shared. In addition, performance of these antibodies such as T cell activation and cytotoxic activities against several antigen specific tumor cells in the various experimental settings will be demonstrated.
10:05 Coffee Break
POSTER SPOTLIGHT PRESENTATIONS
10:35 Discovery and Characterization of a High Potency Anti-Inflammatory Trispecific TNFα/IL-17A/IL-17F Inhibitor
Pavel Yakovlev, Ph.D., Director, Computational Biology, BIOCAD
10:50 Generation of a Two-in-One Antibody Targeting CEA and the αvβ6 Integrin
Enrique Miranda Rota, Ph.D., Postdoc, Oncology, UCL Cancer Institute
11:05 Optimization of Heterodimeric Assembly of Asymmetric Bispecific Antibodies by Protein Engineering and Expression Control
Jeonghoon Sun, Ph.D., Principal Scientist, Biotherapeutics, Celgene Corporation
Optimization of asymmetric IgG-like bispecific antibodies by protein engineering and expression control will be presented. Biophysical, biochemical and/or biological data sets will be accounted for.
11:35 ADAPTIR Immunotherapeutics: A Unique Platform for Engaging T Cells
John W. Blankenship, Ph.D., Lead Scientist, Molecular Biology and Protein Engineering, BioSciences Division, Emergent BioSolutions
Emergent’s ADAPTIRTM (modular protein technology) platform of bispecific protein therapeutics has unique and distinguishing properties, such as redirection of T cell cytotoxicity with induction of minimal cytokine release compared to other formats. A pipeline of ADAPTIR therapeutics is currently under development from early discovery to clinical stage, targeting both solid and hematologic malignancies. Case studies will be presented for the development of two ADAPTIR therapeutics - MOR209/ES414 and ES425.
12:05 pm Chairperson’s Remarks
Eric Smith, Ph.D., Associate Director, Bispecifics, Regeneron Pharmaceuticals
12:10 Case Study: Engineering of a Tetraspecific Anticalin Scaffold to Combat Pseudomonas Aeruginosa Infections
Carsten Corvey, Ph.D., Project Leader, Global Biotherapeutics, Sanofi-Aventis Deutschland GmbH
Highly specific Anticalin® binders were selected and further engineered against all iron-binding siderophores (Pvd I, Pvd II, Pvd III or Pch) of Pseudomonas aeruginosa. In this talk, we will show how siderophores-specific Anticalin proteins can possibly be used in the management of cystic fibrosis patients chronically infected by P. aeruginosa in order to improve lung health and safeguard the quality of life of patients.
12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
1:10 Refreshment Break
1:40 A Tale of Two Bacteria: Developing Bispecific Antibody Drugs for Pseudomonas aeruginosa and Clostridium difficile
G. Jonah Rainey, Ph.D., Senior Scientist, ADPE, MedImmune, LLC
Pathogen-specific therapeutic strategies are gaining prominence as the antibiotic resistance crisis continues to grow. Ultra-narrow spectrum drugs provide unmet medical needs without contributing to broad antibiotic resistance. Given the adaptive nature of microbes to acquire resistance, two critical survival determinants often need to be targeted. A comprehensive strategic approach to select the most appropriate antibody technology platform given the target and pathogen will be described.
2:10 Bispecific Antibodies Perform a Disappearing Act
Katherine Cygnar, Ph.D., Staff Scientist, Genome Engineering Technologies, Regeneron Pharmaceuticals, Inc.
Herein we will present a novel method to block or destroy a target when the canonical blocking antibody approach has proved insufficient. We show that by using a bispecific antibody to couple a target to an internalizing ‘effector’ protein we are able to drive internalization and clearance of a target protein in vitro and in vivo. Several applications will be discussed.
2:40 Unique Application of Bispecific Antibody for Non-Oncology Disease Area
Shinya Ishii, Ph.D., Research Scientist, Research Division, Chugai Pharmaceutical Co., Ltd.
This talk will demonstrate two unique applications of bispecific antibody for non-oncology disease area. First application is a bispecific antibody against activated factor IXa and Factor X that mimics factor VIII function for the treatment of hemophilia A. Second application is biparatopic antibody against soluble antigen with pH dependent antigen property to accelerate the antigen clearance from plasma. Molecular design and in vivo data will be presented.
3:10 Synergy Generates Picomolar Potency and A High Resistance Barrier in Combinectin: A Novel Trispecific HIV-1 Entry Inhibitor with Clinical Promise
Jonathan H. Davis, Ph.D., Principal Scientist, Molecular Structure and Design, Bristol-Myers Squibb
We have designed a biological HIV-1 entry inhibitor with three linked active domains (two Adnectins and a helical peptide) that have separate inhibitory actions. Each of the individual components has an EC50 in the low nM range, but when fused into a single molecule, two different synergistic mechanisms enhance the potency by up to 100-fold or more, with a concomitant boost in the resistance barrier. We describe the design and optimization of the Combinectin, and discuss the general principal of how symmetric and asymmetric synergy can be used and combined to create extremely potent therapeutics.
3:40 End of Engineering Bispecific Antibodies