Cambridge Healthtech Institute’s Inaugural
Bispecific Antibody Design and Applications
Maximizing I-O Therapeutic Potential with Novel Platforms
11-12 March, 2020
As a growing class of immunotherapies, 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, better understanding of their mechanism of action, along with the combination selection of targets. Cambridge Healthtech Institute’s Inaugural Bispecific Antibody Design and Applications will focus on the challenges of bispecific development and their applications for immuno-oncology therapies including cytotoxic effector cell redirecting such as T-cell and NK-cell engagers, enhancing the efficacy and internalization of antibody-drug-conjugates
(ADCs) and many more.
Final Agenda
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WEDNESDAY 11 MARCH
11:15 Organizer’s Remarks
Ngoc ‘Emily’ Le, PhD, Conference Producer, Cambridge Healthtech Institute
11:20 Chairperson’s Remarks
Andrew Sewell, PhD, Distinguished Research Professor and Wellcome Trust Senior Investigator, Infection & Immunity, Cardiff University School of Medicine
11:30 Strategies to Improve Antitumor Efficacy of Genetically Engineered T Cells
Stanley Riddell, MD, Scientific Director, Clinical Research, Fred Hutchinson Cancer Research Center; Professor, University of Washington School
of Medicine
Immune cells can be readily genetically modified to express natural tumor targeting antigen receptors or synthetic chimeric antigen receptors (CARs) that activate immune cell signaling pathways to result in destruction of tumor cells expressing the relevant
target molecule. The presentation will discuss advances in our understanding of receptor signaling and the development of strategies that combine therapeutic agents to improve efficacy and safely extend the spectrum of cancers that can be treated
with cell therapies.
12:00 PD-1 Antibodies Are Transforming Cancer Treatment
Roy D. Baynes, MD, PhD, Senior Vice President and Head, Global Clinical Development, CMO, Merck Sharpe & Dohme
PD-1 antibodies have shown significant activity as monotherapy across multiple cancer types and lines of therapy. Precision medicine tools have been used to identify subjects most likely to respond to PD-1 antibody monotherapy, to provide insight to potential
resistance mechanisms, and to inform combination therapies. A number of these combinations have demonstrated significant activity in additional tumor types and lines of therapy.
12:30 Enjoy Lunch on Your Own
13:30 Chairperson’s Opening Remarks
Paul Widboom, PhD, Associate Director, Antibody Discovery, Adimab LLC
13:35 KEYNOTE PRESENTATION: Current Landscape and Outlook of Bispecific Antibody
Roland Kontermann, PhD, Professor, Biomedical Engineering, Institute of Cell Biology and Immunology, University of Stuttgart
Bispecific antibodies have experienced a dramatic interest and growth for therapeutic applications, with more than 80 molecules in clinical development; e.g., in oncology, immuno-oncology, but also for non-oncology applications. An overview will be given
on the making of bispecific antibodies and the various therapeutic concepts and applications, e.g., for dual targeting strategies, retargeting of immune effector cells, and substitution therapy by mimicking the function of natural proteins.
14:05 Functional Screening Unlocks the Therapeutic Potential of Bispecific Antibodies
Henrike Veninga, PhD, Senior Scientist, Research, Merus
Case studies of clinical assets will be discussed that highlight the role of empirical functional screening. Examples will include both I-O and targeted therapies demonstrating that diverse functional readouts can be incorporated into bispecific antibodies
screens.
14:35 Development and Application of Innovative Immuno-Oncology Mouse Models
Shiying Guo, PhD, Study Director, Pharmacology & Phenotyping, GemPharmatech Co., Ltd.
Mouse is the most commonly used animal model in preclinical evaluation of new drugs. However, with lacking human drug targets and human immune cells, mouse cannot be directly used for preclinical study of macromolecular drugs such as antibodies. Genetic
modified mouse model through human gene replacement and immune reconstituted NCG mouse developed by engraftment of human PBMC or CD34+ HSC can exactly solve this problem, which make them the powerful tools for pharmacological effect studies.
15:05 Refreshment Break in the Exhibit Hall with Poster Viewing
15:45 Selection-Based Development of a Heavy Chain-Light Chain Pairing Technology
Paul Widboom, PhD, Associate Director, Antibody Discovery, Adimab LLC
A significant challenge in the development of multivalent bispecific antibodies involves solving the “heavy chain-light chain pairing problem.” While most heavy chain-light chain pairs possess a preference for their cognate partner, noncognate
mispairing occurs. Avoiding these undesired mispairs is a relevant challenge in the field of bispecific antibody manufacturing. Here we present a solution to the heavy chain-light chain problem derived from a novel selection system. This system
finds mutations that improve cognate heavy chain-light chain pairing while maintaining antigen binding affinity.
16:15 CrossMabs, Fusions and DutaFabs: An Update on Roche’s Bispecific Platforms
Marlon J. Hinner, PhD, Principal Scientist, Group Leader Phage Display, Large Molecule Research, Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich
Bi- and multispecific antibodies facilitate novel modes of action for the treatment of diseases including but not limited to immuno-oncology and autoimmunity. With multiple bispecifics programs in pre-clinical and clinical development, Roche is constantly
increasing its experience and expertise in this area. In this presentation, an update on new and existing bispecific antibody formats and their applications will be provided.
16:45 Selective Inhibition of the Ubiquitously Expressed Immune Checkpoint CD47 on Cancer Cells with Bispecific Antibodies
Stefano Majocchi, PhD, Therapeutic Program Lead, Light Chain Bioscience
Up-regulation of CD47 is an immune evasion mechanism used by both solid and hematological cancers which is generally associated with poor clinical outcome. In the past years CD47 has become the focus of various therapeutic approaches, but because
of the ubiquitous expression of CD47, molecules which cannot discriminate between on-tumor and off-tumor CD47 were shown to result in poor pharmacokinetic properties and/or hematological toxicities. By designing bispecific antibodies with unbalanced
affinity for CD47 and for selected Tumor Associated Antigens (TAA), we can selectively target CD47 on TAA-expressing tumor cells, resulting in potent anti-cancer efficacy both in vitro and in vivo while retaining favorable pharmacological and toxicology profiles.
17:15 Problem Solving Breakout Discussions (See complete list of Problem-Solving Breakout Discussion)
Immunogenicity of Bispecific Antibodies
Moderator: Anne Mansson-Kvarnhammar, PhD, Senior Scientist, Alligator Bioscience AB
- What challenges could one expect for novel bispecific scaffolds in terms of immunogenicity?
- What can be done to test this early to avoid immunogenicity in the clinic?
- What is the usefulness and “predictability” of in silico and in vitro assays to predict clinical immunogenicity of IO antibodies?
Going Beyond Bispecifics – Trispecific Antibodies and Other “Multispecific” Approaches
Moderator: Matthew J. Bernett, PhD, Director, Protein & Antibody Engineering, Xencor, Inc.
- What are the opportunities for using multispecifics
- What challenges would one expect for multispecifics
- Which benefits are expected when using multispecifics
- Which approaches are enabled by multispecifics and which ones remain impossible?
18:15 Dinner Short Course Registration
18:45 Dinner Short Course
Recommended Short Course*
Dinner SC3: Engineering of Bispecific Antibodies and Multi-Specific Non-Antibody Scaffolds - LEARN MORE
Mathieu Cinier, PhD, Scientific Director, Affilogic
Mattias Levin, PhD, Senior Scientist, Antibody Engineering, Alligator Bioscience AB
*Separate registration required.
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THURSDAY 12 MARCH
8:00 Registration and Morning Coffee
8:30 Chairperson’s Remarks
Matthew J. Bernett, PhD, Director, Protein & Antibody Engineering, Xencor, Inc.
8:35 Advancing T Cell Engaging Bispecific Antibodies and Optimized Cytokines for Immuno-Oncology
Matthew J. Bernett, PhD, Director, Protein & Antibody Engineering, Xencor, Inc.
Xencor has applied its XmAb bispecific technology platform to create multiple novel modalities for modulating T cells. These include tumor-associated antigen x CD3 bispecifics for mediating cytotoxicity against tumor cells, dual checkpoint inhibitor
bispecifics for T cell derepression, and a bispecific that combines checkpoint blockade and costimulation. Additionally, we have utilized our heterodimeric Fc domain to create novel long-acting cytokine Fc-fusions for expanding T cells.
9:05 Advances in Immunotherapy: Maximizing T Cell Responses with Tumor Antigen Directed Bispecific Antibodies and Co-Stimulation
Maria Karasarides, PhD, Executive Director, ImmunoOncology, Regeneron Pharmaceuticals
Immunotherapy has advanced as an integral cancer treatment modality primarily from the survival outcomes observed from checkpoint inhibition (α-CTLA-4, α-PD-1, α-PD-L1). While the benefits from checkpoint inhibition are evident,
long term survival is enjoyed by only a small proportion of cancer patients harboring immune-responsive tumors. In this talk we will (1) review the long term survival outcomes provided by checkpoint inhibition (2) discuss immunotherapy combination
strategies and outcomes to date (3) explore potential of achieving maximal T cell responses through the use of tumor antigen directed bispecific antibodies and co-stimulation to address the unmet need remaining for cancer patients with immune-response
and non-responsive tumors.
9:35 Sponsored Presentation (Opportunity Available)
10:05 Coffee Break in the Exhibit Hall with Poster Viewing
10:15 Speed Networking in the Exhibit Hall
10:45 Chairperson’s Remarks
Julian Andreev, PhD, Research Fellow, Oncology & Angiogensis, Regeneron Pharmaceuticals, Inc.
10:50 ZW49 – A Novel Bispecific Antibody-Drug Conjugate (ADC) Targeting HER2-Expressing Cancers
John Babcook, PhD, Senior Vice President, Discovery Research, Zymeworks
ZW49 is a bispecific anti-HER2 ADC currently being evaluated in a Phase I clinical trial. In preclinical studies, ZW49 demonstrated complete tumor regressions in a panel of high and low HER2-expressing patient-derived xenografts, and promising
efficacy in a model of breast cancer brain metastases at exposures tolerated in non-human primates. These results compared favorably when benchmarked against approved and leading HER2 ADCs in clinical development.
11:20 Bispecific ADCs Targeting HER2: Intracellular Trafficking of the Antibody Dictates the Choice of Linker-Payload
Julian Andreev, PhD, Research Fellow, Oncology & Angiogensis, Regeneron Pharmaceuticals, Inc.
Bispecific ADCs bridging HER2 and high turnover proteins travel to lysosomes and improve efficacy of HER2 ADCs with stable linker-DM1. Biparatopic HER2 ADCs induce target recycling and require cleavable linker for greater efficacy. Combining various
bispecific antibody approaches with correct linker-payload technology may allow to generate ADCs with better efficacy and safety profiles.
11:50 Site-Selective Antibody Conjugates by Disulfide Bridging and Cysteine-to-Lysine Transfer
Jamie Baker, PhD, Chemistry, University College London
The selective chemical modification of specific amino-acid residues in antibodies and antibody fragments is likely to form the basis of the next generation of ADCs, and also offer the prospect of chemical bispecifics and related conjugates. In
this talk, two different strategies will be presented for the construction of highly homogenous conjugates from native antibodies, precluding the need for engineering. The first strategy involves targeting the interchain disulfide bonds with
bridging reagents. This has been exploited to generate potent ADCs, bispecific conjugates and even trispecifics. The second strategy we have recently pioneered involves the use of cysteine residues as temporary hooks, delivering conjugation
reagents to specific lysine residues. The resultant lysine conjugates are site-selective and offer the advantage of generating clinically validated, robustly stable, amide linkages.
12:20 Networking Lunch in the Exhibit Hall with Poster Viewing
13:05 Chairperson’s Remarks
Dimitris Skokos, PhD, Director, Immunity & Inflammation, Regeneron Pharmaceuticals
13:10 A Novel Class of Fully Human Co-Stimulatory Bispecific Antibodies for Cancer Immunotherapy
Dimitris Skokos, PhD, Associate Director, Immunology & Inflammation, Regeneron Pharmaceuticals
T cell activation is initiated upon binding of the T cell receptor (TCR)/CD3 complex to peptide-MHC complexes (“signal 1”); activation is then enhanced by engagement of a second “co-stimulatory” receptor, such as the CD28
receptor on T cells binding to its cognate ligand(s) on the target cell (“signal 2”). Recently described CD3-based “bispecific antibodies” act by replacing conventional signal 1, linking T cells to tumor cells by binding
a tumor-specific antigen (TSA) with one arm of the bispecific, and bridging to TCR/CD3 with the other.
13:40 CB213: A Trispecific Dual Checkpoint Inhibitor Optimally Configured for Therapeutic Efficacy
James Legg, PhD, Senior Vice President, Research, Crescendo Biologics
CB213 is a tetravalent trispecific molecule generated using fully human VH domains (Humabody VH) The talk will describe the identification and characterisation of CB213 which delivers dual checkpoint blockade through inhibition of PD-1 and Lag3.
Data will be presented showing that this molecule is able to reverse the dysfunctional phenotype of patient derived human T cells which are non-responsive to clinical PD1 antibodies.
14:10 ATOR-1015 – From Discovery to the Clinic
Anne Mansson-Kvarnhammar, PhD, Senior Scientist, Alligator Bioscience AB
ATOR-1015 is a tumor-directed CTLA-4 x OX40 bispecific antibody designed to improve the efficacy and safety of current CTLA-4 targeting therapies. This talk will cover preclinical in vitro and in vivo data and give an overview of the ongoing Phase 1 study and the clinical development path.
14:40 Managing T Cell Activation and Macrophage Differentiation with a Dual Player Nanofitin to Treat Cancer
Mathieu Cinier, PhD, Scientific Director, Affilogic
Success of immune check point inhibitors highly depends of the number of T cell infiltrates as well as other factors such as inflammatory markers (e.g.; macrophage differentiation). We demonstrated the efficacy of a combination targeting several
immunology pathways to treat cancer.
15:10 Close of Summit
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