engineering bispecifics for improved targeting

Engineering Bispecifics at PEGS Europe 2019 presents truly novel engineering approaches such as new high throughput screening for target discovery, synergistic pair combinations and key bispecific parameters. In addition, engineering for improved targeting with proven functionality, enhanced potency and minimal tox will be showcased. It focuses on challenging areas such as crossing the blood brain barrier, ophthalmology, overcoming bacterial and viral resistance, and Treg selection. We present data-rich case studies that report on difficulties encountered and overcome.

Final Agenda


13:00 Registration (Foyer A)

13:15 Dessert Break in the Exhibit Hall with Poster Viewing (Rio Pavilion)

Auditorium VII

14:00 Chairperson’s Opening Remarks

Mark Chiu, PhD, Associate Director, BioTherapeutics Analytical Development, Janssen Research & Development LLC

14:05 KEYNOTE PRESENTATION: Turning Receptors Off and On with Bispecific Agents: Mechanistic Insights from Biophysics and Biochemistry

Andreas Plückthun, PhD, Professor & Director, Biochemistry, University of ZurichAndreas Plückthun, PhD, Professor & Director, Biochemistry, University of Zurich

Seemingly similar bispecific molecules, binding to the same receptors, can show very different biological behavior with dramatic consequences for their therapeutic suitability. Thus, bispecific agents may affect in opposite ways interaction with neighboring receptors, downstream signaling, internalization and subsequent degradation. A series of advanced biophysical methods have been developed to shed light on these phenomena, laying out blueprints for designing effective therapeutics.

14:35 Lisbon Wasn’t Built in a Day – Alternative Scaffolds Gain Momentum

Binz_kasparH. Kaspar Binz, PhD, Binz Biotech Consulting

The advent of alternatives to antibodies has been observed with large skepticism by the mAb community. It was while turning the academic ideas into businesses that the differentiating strengths of novel scaffolds crystallized. With safety doubts dispelled with clinical data, we now start to see alternatives to antibodies deliver differentiated drugs addressing unmet medical need in novel ways.

Immatics-Biotechnologies 15:05 TCER® Platform: Targeting Of Tumor-Specific HLA Ligands Using T CellReceptor Bispecifics

Bunk_SebastianSebastian Bunk, PhD, Immunology, Immatics Biotechnologies GmbH

Bispecific T cell-engaging receptors (TCER®) are soluble fusion proteins consisting of an affinity-maturated T cell receptor targeting human leucocyte antigen-bound peptides and an antibody for recruitment of T cells and half-life prolongation. The design of the potent TCER molecules allows redirection of human T cells towards peptide-HLA targets showing highly selective expression in tumor tissue as validated by our target discovery engine, XPRESIDENT®. We present data supporting proof-of-concept of this novel class of T cell engagers.

15:35 Networking Refreshment Break (Foyer D)

Auditorium VII

16:00 A Simple IgG-like Discovery Platform for a Complex IgG-like (1+1) Format

Cebe_RegisRégis Cebe, MSc, Scientific Technical Leader, Novartis Biologic Centre, Novartis Institute of Biomedical Research

A variety of bispecific antibody formats are being developed at Novartis. The IgG-like (1+1) format is often preferred when maximal tolerability is in focus. Over the past years, we have been developing a technology platform that enables efficient discovery, engineering, and production of such bispecific format. Based on illustrative case studies, the power of this platform in advancing therapeutic bispecific projects will be highlighted.

16:30 A New Platform for the Identification of Synergistic Bispecific Combinations

Ulrich BrinkmannUlrich Brinkmann, PhD, Expert Scientist, Large Molecule Research, Roche Pharma Research & Early Development, Roche

Bi- and multispecific antibodies enable the exploration of new biological concepts and treatment strategies. Within Roche such next generation biologics have found broad application prospects in various disease areas. The presentation will focus on how format matters when designing multispecific onco-immunological antibodies and how this affects its biological activity, and a novel large-scale combinatorial platform to rapidly generate bispecific antibodies of different format and with different binders.

17:00 End of Day

17:00 Dinner Short Course Registration*

17:3020:30 Dinner Short Courses

Recommended Short Course*

SC10: Engineering of Bispecific Antibodies and Multi-Specific Non-Antibody Scaffolds - LEARN MORE

*Separate registration required.


08:00 Registration (Foyer A) and Morning Coffee (Foyer D)

Auditorium VII

08:30 Chairperson’s Remarks

H. Kaspar Binz, PhD, Binz Biotech Consulting

08:35 Multi-Specific Agent to Overcome Potential Resistance to Influenza

Chiu_MarkMark Chiu, PhD, Associate Director, BioTherapeutics Analytical Development, Janssen Research & Development LLC

A multi-specific agent was designed to target multiple epitopes on pan influenza strains. The engineering to prepare the relevant therapeutic product profile involving viral neutralization, immune effector function, and optimal pharmacokinetic profile will be presented.

09:05 Brain Penetrant Bispecific Agonist Antibodies to Neurotrophin Receptors Trkb and Trkc

Walsh_FrankFrank S. Walsh, PhD, CEO, Ossianix, Inc.

Neurotrophins are attractive therapeutic targets for neurodegenerative disease, but their utility has been restricted by an inability to deliver therapeutic levels of the natural ligands, such as BDNF and NT3, to the CNS . We have used agonist antibodies to the receptors TrkB and TrkC and made them brain penetrant using VNARs to the transferrin receptor. The bispecific antibodies retain agonist activity in vitro and in vivo.

09:35 Preclinical Development of Xmab27564, a Long-Acting IL2-Fc Fusion Protein, as a Novel Treg-Selective Therapy for Autoimmune Diseases

Schubbert_SuzanneSuzanne Schubbert, PhD, Lead Scientist, Cell Biology, Xencor, Inc.

Regulatory T cells are critical for maintaining immune homeostasis, and their deregulation is associated with autoimmunity. Low-dose IL-2 is used therapeutically to expand Tregs, but suffers from rapid clearance and a narrow therapeutic index. To solve these problems, we developed XmAb27564, an IL2-Fc fusion protein with reduced potency and longer persistence. XmAb27564 selectively expands Tregs in human PBMCs in mice and monkeys, supporting its clinical development in autoimmune diseases.

10:05 Networking Coffee Break (Foyer D)

Auditorium VII

10:35 Bispecific Target Discovery by High-Throughput Functional Screening

Bhatta_PallaviPallavi Bhatta, PhD, Principal Scientist, Bispecific Target Discovery, UCB

To exploit the potential of bispecific antibodies to discover new target pairs and invoke novel biology, we have developed technology that enables unbiased functional screening with large, combinatorial panels of bispecific antibodies. Our novel mix-and-match bispecific format allows grid-screening of thousands of bispecifics to hundreds of antigen combinations in high-throughput, disease-relevant assays. We will describe the discovery of several ‘obligate’ bispecifics across multiple disease areas, including autoimmunity, fibrosis, and oncology.

11:05 NestLink Technology to Determine Key Pharmacokinetic Parameters of Hundreds of Bispecifics Simultaneously

Egloff_PascalPascal Egloff, PhD, Platform Leader, Medical Microbiology, University of Zurich

NestLink enables the simultaneous characterization of thousands of different binding proteins without the need to handle individual clones at any stage of the process. The technology was previously applied in vitro for the efficient identification of high-affinity binders against integral membrane proteins in the cellular context. In this talk, I will show that NestLink can be applied in vivo as well, such as to simultaneously determine pharmacokinetic parameters of more than one hundred individual bispecific binding proteins in a single model organism.

Selexis 11:35 Next-Generation CLD Platform for Advanced Bispecific Antibodies Expression

Severine FageteSeverine Fagete, PhD, Director, Cell Line Services, Selexis SA

Despite technologies that have advanced the forced heterodimerization of bi-specific antibodies (bsAb) and innovative purification procedures that remove homodimer by-products, new solutions that improve the bsAb production during the cell line development step are still needed. Here, we present a breakthrough cell line development platform using a single-cell system to express any bsAb format. Scalability and stability issue will be discussed and a case study of rescued bsAb program originally poorly expressing will be presented.

12:05 Problem-Solving Breakout Discussions with a Light Snack 

TABLE 25: Current and Upcoming Strategies to Screen Pharmacokinetic Parameters of Bispecifics

Moderator: Pascal Egloff, PhD, Platform Leader, Medical Microbiology, University of Zurich

  • Conventional PK determination approaches and their limitations
  • Technical requirements for different scaffolds
  • HTP-PK determination technologies: How big is the need?
  • Benefits of engineered peptide barcodes for HTP-PK determination via LC-MS/MS

TABLE 26: Strategy for Engineering and Design of Bispecific Products

Ulrich Brinkmann, PhD, Expert Scientist, PRED, Roche

  • Bispecific antibody platforms, strengths and challenges
  • Criteria for selecting bispecific antibody leads
  • Emerging issues with bispecific antibodies and how to deal with them
  • Next generation(s) of T-cell recruiting bsAbs

TABLE 27: Novel Scaffolds as Multi-Functional Drugs

H. Kaspar Binz, PhD, Binz Biotech Consulting

  • Key strength of alternatives to antibodies
  • Benefits to be expected in research and development
  • Status of clinical validation
  • Enablement of novel therapeutic concepts

Auditorium VII

13:00 Chairperson’s Remarks

Annelise Vuidepot, PhD, Vice President, Pipeline Research, Immunocore

13:05 Specificity of Bispecific T Cell Receptors (TCR) and Antibodies Targeting Peptide-HLA

Vuidepot_AnneliseAnnelise Vuidepot, PhD, Vice President, Pipeline Research, Immunocore

Maintaining peptide selectivity is essential for the development of therapeutic agents targeting peptide-HLA complexes on cancer cells. Using multiple approaches, we assessed the selectivity of two novel classes of T cell redirecting pHLA-targeting bispecifics based on TCR-mimic antibodies or high-affinity TCRs. We show that peptide selectivity is associated with a broad and balanced energetic binding observed predominantly in TCR-pHLA interactions, whereas higher levels of cross-reactivity are associated with more focused ‘hotspot’ binding.

13:35 Dual Agonist Bispecific Antibody Targeting OX40 and CD137 Mediates Anti-Tumour Immunity and Synergises with PD-1/PD-L1 Blockade to Improve Survival in a Syngeneic Mouse Model

Omer Stern, PhD, Discovery, F-star

CD137 (4-1BB) and OX40 are key mediators of costimulatory signals and they play important roles in driving anti-tumour immunity, but combination of CPI with costimulatory agonists has not delivered significant clinical benefit. The activity of Fcγ receptor-dependent agonists may be limited by suboptimal costimulation of T cells and inadequate clustering via Fcγ receptors. We have developed FS120, a dual agonist bispecific antibody that drives potent activation of T cells via co-engagement of CD137 and OX40 and independent of Fcγ receptor binding.

14:05 Optimization of Preclinical Safety and Efficacy of Anti-HER2/CD3

Junttila_TeemuTeemu Junttila, PhD, Senior Scientist, Translational Oncology, Genentech, Inc.

Systemic cytokine release and on-target/off-tumor toxicity on normal tissues are the main adverse effects limiting the applicability of T cell-redirecting bispecific antibodies. We have investigated how affinity to HER2 and CD3 impacts anti-tumor efficacy, distribution, and pre-clinical safety of anti-HER2/CD3 TDB and describe that affinity has a major impact on tolerability. Our studies suggest that fine-tuning the affinities to both the antigen and CD3 is likely critical to maximize therapeutic index in clinical use.

14:35 Concept to Clinic: Development of Fc-containing XmAb Bispecific Antibodies for Immunotherapy

Umesh Muchhal, PhD, Director, Molecular Biology & Protein Sciences, Xencor, Inc.

We present a robust and modular heterodimeric Fc platform, engineered for efficient development of bispecific antibodies and Fc fusion therapeutics. These XmAb bispecific molecules are effective, stable, and easy to manufacture, and allow for the design of potent and/or tunable molecules with enhanced therapeutic index and safety profile. Several tumor-targeting CD3 bi-specifics and dual checkpoint-blocking molecules developed using this platform are in early clinical testing.

15:05 Engineering Mono- and Multi-Valent Inhibitors on a Modular Scaffold

Aurora Diamante, Scientist, Pharmacology, University of Cambridge

We have exploited simple, ultrastable, modular architecture of consensus-designed tetratricopeptide repeat proteins (CTPRs) to build a platform capable of displaying single and multiple functions with diverse geometrical arrangements. Our results point to the tremendous potential of the CTPR platform to exploit the 100,000+ SLiMs in the human proteome and build synthetic protein binders with multi-valent and multi-specific capabilities arrayed with precise pre-programmed geometries.

15:35 End of Engineering Bispecifics