Cambridge Healthtech Institute’s Seventh Annual
Bispecifics and Novel Biotherapeutics

Platform Development, Structure/Function Relationship, and Target and Target Pair Selection

4-5 November 2015

Bispecifics and Novel Biotherapeutics focuses on exciting new engineering platforms and approaches for bispecifics, scaffolds and other novel products. Research for the conference with industry leaders and academics indicated a huge interest in platform developments and overcoming engineering challenges as well as reasons for choice of targets, synergism between them and the importance of the proximity of the two binding sites. Further strong interest was shown in means of enhancing PK profiles, efficacy and stability, as well as manufacturability, and resistance to aggregation and immunogenicity. These are all covered in depth at this event. This conference track also presents preclinical developments and, most importantly, evidence for safety and efficacy.

Final Agenda

Day 1 | Day 2 | Speaker Biographies | Download Brochure

: Unpublished Data | : Case Study

Wednesday, 4 November

07:45 Registration and Morning Coffee

BISPECIFIC PLATFORMS

08:30 Chairperson’s Opening Remarks

Jonas V. Schaefer, Ph.D., Head, High-Throughput Binder Selection Facility, Biochemistry, University of Zurich

09:20 Seamless Bispecific Antibody Discovery and Development Using the Duobody Platform: An EGFR x cMet Case Study

Janine Schuurman, Ph.D., Vice President, Research, Genmab B.V.

The DuoBody platform represents a novel and elegant post-production technology for the generation of stable bispecific antibodies. General strategies, and considerations, for bispecific antibody discovery will be discussed. The suitability of the DuoBody platform for bispecific discovery approaches, showing the importance of doing this in the final format - illustrated by surprising findings, will be shown in a case study selecting a lead cMetxEGFR bispecific antibody.

09:50 Generation, Novel Insights and Clinical Update of Factor VIII Mimetic Bispecific Anti-Factor IXa/Factor X IgG Antibody

Tomoyuki Igawa, Ph.D., Group Manager, Discovery Research, Chugai Pharmaceutical

ACE910 is a humanised anti-factors IXa and X bispecific IgG that places two factors into proximity and mimics factor VIII function for treating hemophilia A overcoming the issues of current treatment. Generation of ACE910, novel insights in unique contribution of non-antigen contacting region on the activity, and interim data of the Phase I and extension study combined will be presented.

10:20 Engineering Next-Generation Biotherapeutics: Developability & Manufacturability

Maria Wendt, Ph.D., Head, Science, Biologics, Genedata

Next-generation biotherapeutics, specifically bi- and multi-specifics, alternative scaffolds, and ADCs, provide significant advantages over traditional IgG-based molecules. However, 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 these candidate therapeutic molecules. We demonstrate the platform’s capability to explore the huge combinatorial space of novel molecule-specific designs, its high-throughput capability, and its built-in tools for developability and manufacturability assessments.

10:50 Coffee Break in the Exhibit Hall with Poster Viewing

11:30 Development of Dual-Targeting Anti-CD47 Bispecific Antibodies

Krzysztof Masternak, Ph.D., Head, Biology, Research, Novimmune SA

Dual-targeting antibodies (kλ-bodies) allow selective CD47 neutralisation in cancer cells expressing a particular cell surface antigen (in this case, CD19 or mesothelin), which is important, given that CD47 is ubiquitously expressed – including in RBC, platelets and other blood cells. I will present recent in vivo and in vitro data showing that our dual-targeting anti-CD47 bispecific antibodies have superior pharmacological properties in the clinic (PK, toxicity, a broad therapeutic window) as compared to monoclonal anti-CD47 antibodies.

12:00 Novel Bispecific Antibodies for Treatment of Chronic Hepatitis B Virus Infection and Associated Tumours

Felix Bohne, Ph.D., Principal Investigator, Institute of Virology, Helmholtz Centre Munich

Chronic hepatitis B is characterised by exhausted effector cells incapable of eradicating the virus. To circumvent this limitation, HBV-specific retargeting of immune effector cells using bispecific monoclonal antibody (BiMab) constructs is a promising therapeutic approach. ScFv-driven tetravalent BiMab showed excellent PBMC-retargeting efficacy and in vitro killing of HBV-transgenic and infected hepatocytes. Translation into a relevant humanised mouse model yielded first proof-of-principle results targeting HBV-positive tumours.

12:30 Creating Focused Libraries for Protein Engineering

Nels Thorsteinson, Scientific Services Manager, Biologics, Chemical Computing Group

Protein engineering plays a pivotal role in modulating the function, activity and physical properties of biologics. Representative strategies employed in protein engineering include directed evolution and rational protein design. Although both approaches are effective at identifying and optimizing protein therapeutic candidates, efficient search and evaluation of an excessively large sequence design space becomes challenging and requires multiple experimental rounds to reasonably assess the sequence space. Here we have developed a computational approach which predicts mutation probabilities for given residue sites in specified sequences. In assessing the probabilities at given residue sites, the sequence search space can be efficiently sampled to design and produce focused mutant libraries.

12:45 Enjoy Lunch on Your Own

TARGET SELECTION AND SPECIFICITY

14:00 Chairperson’s Remarks

Ulrich Brinkmann, Ph.D., Expert Scientist, Roche Pharma Research & Early Development, Roche Innovation Center, Penzberg

14:05 Improved Binder Specificity by Using Structural Epitope Recognition

Jonas V. Schaefer, Ph.D., Head, High-Throughput Binder Selection Facility, Biochemistry, University of Zurich

Specificity is a major challenge in the usage of affinity reagents for both therapeutic and diagnostic applications. Using our binder selection pipeline and novel ways of target presentation, we were able to tackle this issue. I will present data on ongoing projects targeting viral infections and neurodegenerative diseases, two fields of applications where target conformation is of critical importance.

14:35 The Use of Serum Compatibility to Select Bispecific Antibodies

Mark Chiu, Ph.D., Associate Director, Multispecific Biologics Engineering, Biologics Research, Janssen Research & Development LLC

Bispecific antibody (bsAb) engineering can change protein symmetry and consequently molecular properties. Characterisations of bsAb in the presence of sera can assess potential self-interaction and interactions between the molecule and serum proteins which can affect PK, efficacy, aggregation, and immunogenicity. We present in vitro biophysical characterisations using spectroscopy and chromatography that can be used in developability to support lead selection.

15:05 High Throughput Approach to Select Synergistic Target Pairs and Bispecific Antibodies

Jijie Gu, Ph.D., Senior Principal Research Scientist, Global Biologics, AbbVie Bioresearch Center

Bispecific antibodies have emerged as one of the important approaches for next generation antibody-based therapeutics. One of the key challenges the bispecific antibody field is facing is how to identify target pairs and bispecific molecules with novel biology. This presentation will discuss a high-throughput approach to identify target pairs and bispecific antibodies with potential synergistic effect.

15:35 Refreshment Break in the Exhibit Hall with Poster Viewing

BISPECIFICS FOR IMMUNO-ONCOLOGY

16:15 Bispecific Anticalin Fusion Proteins for Localised Targeting of Immune Cells for Application in Immuno-Oncology

Christine Rothe, Ph.D., Vice President, Discovery & Alliance Management, Pieris Pharmaceuticals, Inc.

Anticalin® proteins are derived from human lipocalins and are about 18 kDa in size. We have generated different bispecific constructs by fusing distinct Anticalin proteins to each other or by fusing Anticalin proteins to antibodies or Fc-domains. These constructs simultaneously bind a tumour and a T cell target and may be able to better control T cell activation in the tumour mircoenvironment. Binding properties, stability and in vitro functionality of bispecific Anticalin fusion proteins are presented.

16:45 The Dual-Dual-Targeting Concept - Enhancing Natural Killer Cell-Mediated Lysis of Lymphoma Cells by Combining Therapeutic Antibodies with Bispecific Immunoligands Engaging NKG2D or NKp30

Matthias Peipp, Ph.D., Group Leader, Stem Cell Transplantation and Immunotherapy, Christian-Albrechts-University of Kiel

Novel bispecific immunoligands were compared for their abilities to boost ADCC in an attempt to design an effective antibody combination strategy. Co-targeting and activating NK cell receptors may represent a promising approach for enhancing the efficacy of therapeutic antibodies. A ‘dual-dual-targeting’ concept by co-targeting two tumour antigens and concomitant engagement of two different activating NK cell receptors is proposed.

18:15 Networking Reception in the Exhibit Hall with Poster Viewing

19:15 End of Day

Day 1 | Day 2 | Speaker Biographies | Download Brochure

Thursday, 5 November

08:00 Morning Coffee

NOVEL APPROACHES FOR ONCOLOGY

08:30 Chairperson’s Remarks

Janine Schuurman, Ph.D., Vice President, Research, Genmab B.V.

08:35 Exploiting the Versatility of Alphabodies to Target the Intrinsic Pro-Survival Protein MCL-1

Yvonne McGrath, Ph.D., CSO, Complix NV

Alphabodies are stable proteins where 70% of residues are amenable to modification by design or library selection. These features have been exploited in the design of Alphabodies which target the intracellular intrinsic pro-survival protein MCL-1. These Alphabodies have been shown to bind specifically to MCL-1 with high affinity and crystal structures obtained. Efficient uptake of the Alphabodies into cells and cell killing of MCL-1 dependent tumour cells has also been demonstrated.

09:05 An Engineered Fc Fragment Targeting HER2 Induces Profound Anti-Tumour Effects through Apoptosis

Sarah Batey, Ph.D., Principal Scientist, Tumour Biology and Protein Science, F-star Biotechnology Ltd.

FS102 is a HER2 specific Fcab™ (Fc fragment with antigen binding) that induces profound HER2 degradation and potent cell apoptosis in tumour cells expressing high levels of the receptor. The efficacy of FS102 in patient-derived xenograft (PDX) models correlates strongly with clinically relevant HER2 biomarkers. We hypothesise that FS102 depletes HER2 which commits the HER2-addicted tumour cells to apoptosis through oncogenic shock. FS102 is currently in Phase I clinical trials.

09:35 Hapten-Directed Spontaneous Disulfide Shuffling: A Universal Technology for Site-Directed Covalent Coupling of Payloads to Antibodies

Ulrich Brinkmann, Ph.D., Expert Scientist, Roche Pharma Research & Early Development, Roche Innovation Center, Penzberg

Hapten-binding antibodies with accessible cysteine in proximity to the binding pocket were designed to covalently attach payloads to the antibody. Payloads carrying thiols become positioned on the antibody and linked by spontaneous redox shuffling. Attachment works with different haptens, antibodies and payloads. Applications include modulation of pharmacokinetics of small compounds as well as payload linkage to targeting vehicles in a reduction-releasable manner.

10:05 An Integrated Approach to Managing Immunogenicity Risk and Drug Immune Modulation

Jeremy Fry, DPhil, Director, Sales, ProImmune

Immunogenicity is one of the most complex issues to address in drug design and development. I will provide an overview of the best tools to mitigate immunogenicity risk, including Mass Spectrometry antigen presentation assays; DC-T and T cell proliferation assays for biologic lead selection/optimization; HLA-peptide binding assays to characterize individual epitopes as well as undiluted whole blood cytokine storm assays.

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

BISPECIFICS FOR ONCOLOGY

 
11:15 Anti-CD20/CD3 T Cell Dependent Bispecific Antibody (TDB) as Potential Therapy for B Cell Malignancies

Diego Ellerman, Ph.D., Senior Research Associate, Protein Chemistry, Genentech, Inc.

The preclinical development of a B cell targeting anti-CD20/CD3 T-cell dependent bispecific antibody (CD20-TDB) will be described. CD20-TDB is highly active in killing B cells in vitro and in vivo as demonstrated in multiple murine models. In cynomolgus monkeys, CD20-TDB potently depletes B cells in peripheral blood and lymphoid tissues while demonstrating PK properties similar to those of conventional monoclonal antibodies.

11:45 Impact of Bispecific and Multi-Specific Molecule Structure on Safety and Efficacy

Tariq Ghayur, Ph.D., Distinguished Research Fellow, DVD-Ig and Novel Biologics, Global Biologics, AbbVie, Inc.

Bi- and multi-specific formats differ in their target binding domain placement, distance and valency. These differences may be critical when targeting cell surface receptors. Therefore, designing the right format to match target and / or target pair biology may be important for selecting therapeutic candidates with desired safety, efficacy and PK profiles.

12:15 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

13:00 Dessert Break in the Exhibit Hall with Poster Viewing

13:30 End of Bispecifics and Novel Products

Day 1 | Day 2 | Speaker Biographies | Download Brochure

: Unpublished Data | : Case Study

Conference Programs

• Display of Biologics
• Engineering Antibodies
• Machine Learning - Part 2

• Antibody-Based Therapies
• Emerging Targets & Approaches
• Membrane Protein Targets

• Safety & Efficacy
• Advancing Bispecifics
• Engineering Bispecifics

• Modulating the TME
• Innovative CAR T Therapy
• Next-Gen Immunotherapies

• Optimisation & Developability
• Analytical Characterisation
• Protein Stability & Formulation

• Data Science & Engineering
• Optimising Expression
• Process Development

• Intro to Machine Learning
• Machine Learning - Part 1
• Machine Learning - Part 2

• Antibody-based Therapies
• Engineering Conjugates
• Next-Gen Immunotherapies