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

WEDNESDAY 11 MARCH

PLENARY KEYNOTE SESSION

11:15 Organizer’s Remarks

Joel Hornby, BSc Hons, Conference Director, Cambridge Healthtech Institute

11:20 Chairperson’s Remarks

Reno Debets, PhD, Professor, Laboratory of Tumor Immunology, PI, Medical Oncology, Erasmus MC-Cancer Institute

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

Kandeepan GaneshalingamKandeepan Ganeshalingam, MD, Executive Director,Therapeutic Area Head Oncology, European Clinical Development Global Clinical Development, MRL, Merck Sharp & Dohme (MSD)

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

15:05 Refreshment Break in the Exhibit Hall with Poster Viewing

BISPECIFIC ANTIBODY DISCOVERY, DESIGN AND OPTIMIZATION

15:40 NEW: Chairperson’s Opening Remarks

Stefano Majocchi, PhD, Therapeutic Program Lead, Light Chain Bioscience

 

15:45 Selection-Based Development of a Heavy Chain-Light Chain Pairing Technology**

Widboom_PaulPaul 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**

Hinner_MarlonMarlon 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

Majocchi_StefanoStefano 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.

THURSDAY 12 MARCH

8:00 Registration and Morning Coffee

T Cell Engagers

8:30 NEW: Chairperson’s Remarks

Stefano Majocchi, PhD, Therapeutic Program Lead, Light Chain Bioscience

8:35 NEW: 4224-A Bispecific Antibody Designed to Prime Neoantigen - Specific T Cells Utilizing Endogenous Tumor Exosomes**

Ellmark_PeterPeter Ellmark, PhD, Assoc. Professor, Vice President Discovery, Alligator Bioscience


9:05 NEW: Pharmacokinetics And Immunogenicity Of Three Anti-HER2/CD3 T Cell Dependent Bispecific (TDB) with Varying Affinities to Their Targets in Cynomolgus Monkeys**

Meric_Ovacik_AyseAyse Meric Ovacik, PhD, Scientist, Preclinical and Translational Pharmacokinetics in Development Sciences, Genentech

The clinical success of heme tumor-targeting TDBs is to be followed solid tumor targeting TDBs. More in-depth tools are needed to be developed for understanding solid tumor targeting TDBs as they required to be distributed to the tissues. We will present a systematic approach to develop a minimal PBPK model of HER 2/CD3 for projecting clinical exposures. 

9:35 NEW: Development and Application of Innovative Immuno-Oncology Mouse Models**

GemPharmatechGuo_ShiyingShiying 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.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

10:15 Speed Networking in the Exhibit Hall

lesson learned in bispecific antibody, characterization and linkers

10:45 NEW: Chairperson’s Remarks

Mathieu Cinier, PhD, Scientific Director, Affilogic

10:50 NEW: Introduction and Overview of Bispecific Antibodies in the Clinic: Learnings from Success and Failures**

Rakesh Dixit, PhD, DABT, President & CEO, Bionavigen

11:20 HIGHLIGHTING POSTER: Characterisation of bsAb Higher-Order Structure Using FPOP-LC-MSMS

Melissa Coxhead, MBMS, Research Assistant, Biomedical Sciences, University of Leeds 

Fast Photochemical Oxidation (FPOP) of Proteins is an emerging technique currently used in mass spectrometry to identify solvent accessible regions of native protein by covalent labelling of side chains. Unlike most other structural proteomics techniques, this approach is also amenable to structural characterization in formulation buffers, or in fact even in vivo. The workflow consists of mixing a protein sample with hydrogen peroxide and a scavenger and feeding it through a UV transparent capillary or cell. A pulsed UV laser irradiates a defined section of the flow and generates hydroxyl radicals in situ with lifetimes of µsec. These radicals can react with almost any of the exposed amino acid side chains, with some residues being particularly reactive. These modifications (mostly +16 Da) can be detected after digestion and LC-MS/MS analysis. Due to the covalent nature of the labels, they are irreversible (unlike HDX) and individual residue resolution can be obtained. The role of FPOP in bio-therapeutic development analysis is being evaluated. The manufacturing process involved with bsAb production is rather tedious and yields of the desired end scaffold are not high. This contribution will demonstrate the beneficial aspects of the method and show the information which can be obtained regarding bsAb structure; which is hoped to reduce the design and manufacturing: molecule-to-market timeline.  

11:35 Site-Selective Antibody Conjugates by Disulfide Bridging and Cysteine-to-Lysine Transfer

Baker_jamieJamie 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.

MaxCyte 12:20 Networking Lunch in the Exhibit Hall with Poster Viewing

BISPECIFIC ANTIBODY AND CHECKPOINT INHIBITOR

13:05 NEW: Chairperson’s Remarks

Mathieu Cinier, PhD, Scientific Director, Affilogic

13:10 NEW: Managing T Cell Activation and Macrophage Differentiation with a Dual Player Nanofitin to Treat Cancer

Cinier_MathieuMathieu 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.

13:40 Combination Immunotherapy: The New Paradigm for the Treatment of Metastatic Melanoma and Renal Cell Carcinomay

John WagstaffJohn Wagstaff, MD, MB ChB, Director, South West Wales Cancer Institute & Professor, Medical Oncology, Swansea University College of Medicine 

Both melanoma and renal cell carcinoma (RCC) has been increasing incidence over the past twenty years. When metastatic disease develops these cancers were notorious for their lack of response to conventional chemotherapy and the prognosis of these patients was poor. The median survivals were between 11 and 13 months. The discovery of anti-CTLA4 (ipilimumab (Ipi)) and anti-PD1 (nivolumab (Nivo)) inhibitory monoclonal antibodies has transformed the prognosis of these patients. The five-year survival of patients with metastatic melanoma is 53% and the survival curve is flat suggesting that these patients may be cured. In RCC the median survival with sunitinib was 26.1 months but the median OS for Ipi+Nivo has not been reached. These impressive results do however come at the cost of autoimmune-related adverse events but despite this quality of life improves with these new therapies. these therapies herald a new era in the treatment of metastatic cancers.

14:10 ATOR-1015 – From Discovery to the Clinic

Mansson-Kvarnhammar_AnneAnne 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 Close of Summit

**Presentations delivered via a live, interactive video conferencing platform.**

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