Thursday, 23 October
8:00 Morning Coffee, Poster and Exhibit Viewing
8:30 Comments by Session Chairperson
8:35 Report Back of Problem Solving Roundtable Groups
9:35 From Antibodies to DARPins
Andreas Plückthun, Professor of Biochemistry, University of Zürich, Switzerland
The immune system has perfected the IgG molecule for its original function. Yet, for out-of-context applications, such as tumor targeting and delivering payloads, we can take the antibody merely as an engineering inspiration, and devise other proteins from first principles. This will discussed using the example of Designed Ankyrin repeat Proteins (DARPins) and their biomedical applications.
IMMUNOGENICITY
10:05 Immunogenicity of Humanised/Fully-Human Antibodies and T Cell Epitopes
Matthew Baker, Ph.D., Chief Scientific Officer, Antitope Ltd.
Helper T cell epitopes are drivers of immunogenicity through induction of class-switched, somatically mutated high affinity antibodies that can bind to the injected therapeutic. For therapeutic antibodies, these occur in the variable region and can be detected in the majority of humanised and fully-human antibodies. One approach for identifying T cell epitopes is in silico prediction of peptide binding to MHC class II (pMHC) and several groups have claimed correlation of high affinity pMHC and T cell epitopes and have proposed the removal of such epitopes or the selection of other lead antibodies without such epitopes. Data will be presented to demonstrate that this approach is flawed as some high affinity pMHC can induce immunological tolerance whilst certain low affinity pMHC result in helper T cell responses. Composite Human Antibodies are created without variable regions T cell epitopes and examples of such antibodies will be presented using in vitro and ex vivo T cell assays to demonstrate absence of T cell epitopes.
10:35 Generating Fully Human Antibodies that are Improved with Respect to Cross Reactivity Profile and Affinity Compared to Existing Murine, Chimeric or Humanized Antibodies
Anita Kavlie, Ph.D., Senior Scientist, Affitech AS
We generated the fully human antibodies r84/PGN311 against vascular endothelial growth factor (VEGF) and 1N11/PGN635 against phosphatidylserine (PS) in complex with b2-GP1. These antibodies were found to show improved cross reactivity profiles, binding affinities and biological activity compared to existing murine, chimeric or humanized antibodies against the same targets.
11:05 Coffee Break, Poster and Exhibit Viewing
11:35 Preclinical Strategies for Immunogenicity Assessment
Philippe Stas, Chief Executive Officer, AlgoNomics
Most therapeutic antibodies in clinical trials or on the market are, to a variable extent, immunogenic. Formation of antidrug antibodies poses a risk that should be assessed during drug development, as it possibly compromises drug safety and alters pharmacokinetics. This presentation addresses the novel regulatory guidelines for immunogenicity assessment in the context of antibody therapeutics. Strategies are presented to optimally assess and control immunogenicity in the lead discovery and preclinical stage.
12:05 Immunogenicity Assay Development & Qualification
Larry Lo, Ph.D., Senior Scientist II, Human Genome Sciences, Inc.
Biopharmaceutical products can induce immune responses leading to clinical consequences varying from loss of efficacy to serious adverse events. Therefore, it is important to develop both a testing scheme and immunogenicity assays able to provide accurate assessments of antibody responses in preclinical and clinical studies. In this presentation we will share experience to develop and qualify Electrochemiluminescence (ECL) immunogenicity assays for our Phase 3 trials.
12:35 Luncheon Technology Workshop (Sponsorship Available) or Lunch On Your Own
CASE STUDIES
14:00 Comments by Session Chairperson
14:05 Targeting Tumor Angiogenesis by Blocking DLL4 and Notch1
Yan Wu, Ph.D, Senior Scientist, Antibody Engineering, Genentech Inc.
Dll4 (ligand) and Notch1 (receptor) are key molecules for angiogenesis. Activation or over-expression of Notch1 is also implicated in many cancers. We have generated functional and cross-species blocking phage antibodies to Dll4 and Notch1. Blocking Dll4 or Notch1 with specific phage antibodies renders endothelial cells hyper-proliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 or Notch1 inhibited tumor growth in several tumor models. Anti-Dll4 has additive effect with anti-VEGF treatment.
14:35 Efficient Cell-Mediated Cytotoxicity Using Bispecific Domain Antibodies for Cancer Therapy
Patrick Chames, Ph.D., Main Scientist, Antibody Engineering and Immunotargeting, CNRS - UPR
We are developing a new generation of nanobody-based bispecific antibodies, easy to produce and capable of circumventing most of the limitations faced by today’s therapeutic antibodies, including Fc receptor polymorphism, glycosylation, competition with endogenous IgG and binding to inhibitory receptors. These new molecules very efficiently trigger NK-mediated tumor cell lysis.
15:05 MEDI-578 (Anti-NGF IgG): Isolation, Multi-Lead Optimization and in Vivo Characterization
Andrew Buchanan, Ph.D., MedImmune Cambridge
NGF is a driver of chronic pain and in this rapidly developing field anti-NGF therapy has shown potential to manage chronic pain. This case study will present the lead generation of a monocolonal antibody neutralising NGF. It will focus on the benefits of MedImmune’s antibody optimisation technology to optimise multiple antibodies in parallel and delivery a candidate drug matching the defined product profile. The in vitro potency characterisation of MEDI-578 will be presented.
15:35 Staphylococcal Surface Display for Protein Engineering and Characterization
John Löfblom, Ph.D., School of Biotechnology, Royal Institute of Technology (KTH)
We have developed a new selection system for protein engineering purposes. The technology is based on display of libraries on the Gram-positive bacterium Staphylococcus carnosus and selection using FACS. We have subcloned and displayed a large library and selected picomolar affinity binders for TNFa. The display system has also been employed for epitope mapping and several new projects are ongoing.
16:05 The Myeloid Cell Surface Receptor IREM-1: A Novel Monoclonal Antibody Target for Acute Myeloid Leukemia Therapeutics
Wouter Korver, Ph.D., Senior Scientist, Nuvelo, Inc.
IREM-1 is an inhibitory receptor expressed on the surface of myeloid cell lineages, including cell lines derived from acute myeloid leukemia (AML) patients. We have generated monoclonal antibodies (mAbs) against IREM-1 and assessed their therapeutic potential for AML. We surveyed expression of IREM-1 in a variety of cell lines as well as in primary cells obtained from AML patients. Selected mAbs were tested in functional complement-dependent cytotoxicity (CDC) assays against AML cell lines and freshly isolated blasts from AML patients. In vivo anti-cancer activity of lead mAbs was demonstrated in an established HL-60 xenograft model. Taken together, these results demonstrate IREM-1 as a potential new target for immunotherapy of AML.
16:35 Closing Comments
16:45 Close of Antibodies Europe Conference