Neil Weir is responsible for global research at UCB. He has been with UCB and Celltech for the past 16 years during which time he has been involved in the discovery and development of antibody and antibody fragment-based drugs along with the development of supporting technologies. He is now focused on Research Portfolio Management and Research Strategy. Prior to joining Celltech Neil, worked in Academic Research on the regulation of amino acid biosynthesis at the University of Kent at Canterbury. Neil is in the Research Director Group of the EFPIA (The European Federation of Pharmaceutical Industries and Associations) and is also a steering group member of the Innovative Manufacturing Research Centre. Neil is also a member of the Translational Medicines Board, established after the Cooksey Review in 2006. He has a BSc (Hons) in biology from Edinburgh University and studied for his PhD at the Institute of Biotechnology (University of Kent at Canterbury) in metabolic flux through amino acid biosynthesis pathways.

For the pharmaceutical industry, success in the clinic should be the ultimate criterion for target validation. However the continued high rate of efficacy failures triggered in many pharmaceutical and biotechnology companies the need to develop a robust target validation strategy before moving molecular targets into drug discovery for a particular disease. Lorenz Mayr will discuss about Novartis’ comprehensive and contemporary framework of approaching target validation in drug discovery through: • Translating and establishing operational excellence from the target validation point of view to increase efficacy and profitability during drug discovery • Adopting multi layer approaches to discharge any unexpected challenges • Exploring new tools and gaining control on gene expression to successfully accomplish a multi disciplinary approach.

A novel activity of human IgG4 was identified by which it is distinguished from all other antibody isotypes: IgG4s are dynamic molecules that undergo Fab arm exchange by swapping an IgG4 heavy chain and attached light chain (half-molecule) for a heavy-light chain pair from another IgG4 molecule (van der Neut Kolfschoten et al. Science, 317: 1554-7.). By this process IgG4 antibodies acquire bispecific binding properties which will, under normal conditions, result in reduced cross-linking ability and reduced immune responses. This process is a continuously ongoing process: the IgG4 repertoire formed will constantly exchange Fab arms which may alter the effect of therapeutic IgG4 antibodies. Data of IgG4 Fab arm exchange, including data showing the engagement of therapeutic IgG4 antibodies (natalizumab) in this reaction in humans, will be shown (Labrijn et al., Nature Biotech. 27:767-71). Our findings have important implications for the pharmacokinetics and pharmacodynamics of IgG4 therapeutics which will be discussed. Dr. Janine Schuurman has been working in the field of recombinant antibodies for about 15 years. In 1997 she got a PhD in Immunology from the University of Amsterdam. During her PhD at Sanquin Research she worked on valency aspects of antibodies within the field of Allergy. During this period, studying the biology of IgG4, she and co-workers discovered that the functional monovalent behaviour of normal human serum-derived IgG4 antibodies was caused by bispecificity of the molecule. Hypothesis on the mechanism behind this were proposed. After a few post-doc positions at Sanquin Research and the University Utrecht she started in 2001 at Genmab. She has been involved in the development of several therapeutic antibodies as scientist or as project manager. Mainly due to her initiative, the research on the peculiar behaviour of IgG4 has been restarted in collaboration between Genmab, Sanquin and the University Maastricht. This research resulted in a Science paper “Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange” followed by a Nature Biotechnology paper “Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo”. This research, relevant for the development of IgG4-based antibody therapeutics, will be discussed during the WDDsummit in CPH. Current research of Janine focuses on Antibody Biology, Immunogenicity and the development of novel antibody formats such as UniBody.

Alan C Rigby Ph.D. Assistant Professor of Medicine Harvard Medical School Center for Vascular Biology Research Division of Molecular and Vascular Medicine Division of Interdisciplinary Medicine and Biotechnology Department of Medicine Beth Israel Deaconess Medical Center The concept of selectively targeting the interaction interfaces of protein-protein and/or protein-DNA complexes represents a paradigm shift in therapeutic strategies aimed at reprogramming gene expression programs deregulated in cancer and inflammation. Protein-protein and/or protein-DNA molecular recognition is the cornerstone of cellular function, mechanistic signal transduction as well as gene expression. We believe that transcription factors represent an important therapeutic target space that has proven difficult to target. However, the need to target transcription factors from what has been coined as the “expanded druggable genome” is now given the significant unmet in cancer and inflammation. We have developed and benchmarked a computer aided drug discovery (CADD) platform for the evaluation of this novel chemical space, which I will discuss. We have implemented our validated platform, which leverages the strengths of in silico structure-based (SB) and ligandbased virtual screening (LBVS) platform and is powered with NMR spectroscopy target validation to interrogate novel chemical space: the transcription factor-DNA interaction interface. I will present SBVS and stringent LBVS scaffold expansion data that builds upon our previous peptidomimetic studies, identifying unique small molecule chemotypes that specifically target these transcription factor-DNA interfaces. The ultimate goal of this program is the identification of small molecule inhibitors that selectively target and disrupt these complex interfaces and data in support of our efforts will be discussed.

Andrew is a Senior Director in the Strategic Management Group at Pfizer Global Research and Development in New London, Connecticut, where his work is focused on approaches to enhance innovation and efficiency across Research and Development. He has 12 years management experience with Pfizer leading large multi-disciplinary departments in Drug Discovery and prior to that was researcher for over 12 years at Cornell Medical College, the American Cyanamid Company and Wyeth. Andrew earned his PhD in Chemistry from the University of Essex in the UK and did his postdoctoral research in the USA at Cornell University Medical College -New York Hospital with Professor Alton Meister.

Indications discovery unit

Alex Haahr Gouliaev is a co-founder of Nuevolution A/S. He served as Vice President, Chemistry and Drug Discovery from 2001 until he was appointed Chief Executive Officer in September 2005. He was previously Director of Medicinal Chemistry, member of the Management group, and a member of the Board of Directors at NeuroSearch A/S. Alex Haahr Gouliaev has 20 years experience in medicinal chemistry, in vitro pharmacology, and process optimization and up-scaling of clinical candidates and technology development. Alex Haahr Gouliaev received his Ph.D. in Medicinal Chemistry from Aarhus University. He has authored or co-authored more than 40 publications and patent applications in the fields of synthetic/medicinal chemistry and CNS pharmacology.

World-Wide Research and Development, Pfizer Ltd, Ramsgate Road,

Chemokines are building blocks of the most versatile, coherently functioning system of intercellular communication. Chemokine binding, to specific receptors unleashes cascades of intracellular secondary mediators that turn on cell-specific intrinsic functional programs, influencing not only chemotaxis but also proliferation, maturation, differentiation, apoptosis, malignant transformation and dissemination. Response of any single cell type to specific chemokine can be different according to the metabolic and differentiation status mode of the cell. The prevention of inflammation through blockade of the chemokines/chemokine receptors system has been recently recognized as a major target for pharmacological intervention. Several evidences suggest that MCP-1/CCL2 plays a major role during inflammatory processes and it has been proposed as a new pharmacological target in various diseases. In vitro and in vivo evidence for a physiopathological relevant contribution was indeed obtained for several and distant inflammatory conditions including renal and vascular diseases, cancer and various other pathologies. Angelini has an ongoing research program on a new class of Chemokine inhibitors : small molecules acting as specific inhibitors of the MCP-1/CCL2 ( and other members of the MCPs family : MCP-1, MCP-2, MCP-3 and MCP-4) production . Bindarit is the most advanced of a group of proprietary compounds acting on the synthesis of MCPs. On this ground Bindarit can be considered a “first in class” small molecule, acting on an intriguing multi-disease target. Indeed, being an orally active compound, Bindarit has potential advantages over chemokine receptor antagonists and anti-MCP-1/CCL2 monoclonal antibodies. Bindarit is an original indazolic derivative endowed with anti-inflammatory activity exerted by the inhibition of up-regulated synthesis of the CC chemokine Monocyte Chemoattractant Protein-1 (MCP-1/CCL2). Recent studies, aiming at molecular details of Bindarit’s mechanism of action, have demonstrated that the product selectively inhibits the mRNA synthesis of the members of monocyte chemotactic protein subfamily of CC inflammatory chemokines (MCP-3/CCL7, MCP-2/CCL8), in addition to MCP-1/CCL2. Bindarit effect on inflammation is neither mediated by arachidonic acid metabolism interference, nor by immunosuppressive effects. In a number of preclinical models of inflammatory conditions involving MCP-1/CCL2, bindarit was demonstrated to exert its anti-inflammatory properties both in a preventive as well as in a therapeutic setting/regimen. Preclinical studies demonstrated that bindarit has a safe toxicological profile and is devoid of immunosuppressive, mutagenic and carcinogenic effects. Phase I clinical studies showed that bindarit is well tolerated in normal subjects and in elderly volunteers (up to 1200 mg twice daily orally, for 12 days) confirming the good tolerability profile, anticipated by preclinical studies. So far, approximately 226 healthy volunteers and 394 patients have been treated with bindarit. Efficacy and safety were assessed in patients with rheumatic disease, lupus nephritis (LN), dyslipidemia, and diabetic nephropathy (DN). Phase II data confirmed the good tolerability profile of the drug and showed efficacy in reducing urinary albumin excretion (UAE) and urinary MCP-1/CCL2 levels in LN patients, and UAE in type 2 diabetic nephropathy patients.

Abstract: Analysis of sequences of VH and VL of the conventional antibodies of llamas and dromedaries reveals a surprising high degree of sequence homology with human segments. In silico prediction suggests identical canonical folds of the CDRs and combinations of these as found in the analogous human germline V regions, thus yielding binding site structures identical as those occurring in human antibodies. This finding encouraged us to explore the possibility of applying camelid derived conventional antibodies as starting point for the generation and development of therapeutic antibodies. Four llamas were immunized with human IL-6 and from the cloned Fab repertoires target specific antibodies were identified. By screening in an IL-6 – IL6R ELISA large panels of competing Fabs could be identified. Sequence analysis revealed the presence of 11 antagonistic antibodies with HCDR3s differing both in length and amino acid composition. The off rates found for these Fabs ranged between 10-4 and 10-5 sec-1. By tapping into the naturally occurring affinity variants family members were discovered with off rates reaching the Biacore sensitivity limit. These leads, when converted into chimeric IgG, turned out to have subpicomolar potencies as measured in the bioassay. The antibodies are at least as potent as or even more potent than heavily in vitro affinity matured antibodies reported in literature. Germlining was performed by substituting the few deviating residues within the framework regions by those occurring in the best matching human germline segments. The identity score of the Framework Regions (typically around 90% for the wild type variable regions) could be improved without loss of affinity and potency to 95 – 99%, what is comparable with antibodies generated by fully human technologies. The active immunization of outbred camelids gives a large diversity of therapeutically active antibodies with extremely good affinities and potencies, and due to the high human sequence homology of the V regions germlining is straight-forward and yields leads indistinguishable from fully human antibodies. Choice in leads increases the chance of a successful clinical development of a therapeutic antibody and therefore we believe that the SIMPLE ANTIBODY™ technology which exploits the conventional antibodies from camelids will transform the discovery and development of therapeutic antibodies.

Many naturally occurring proteins have pharmacologically useful properties. However, several proteins need to be re-designed and optimized to be suitable as drugs, irrespective of their origin being microbial, human or from other sources. The in vitro evolution technology FIND® is an efficient tool for this since it can be utilized to redesign and optimize virtually any characteristic of a protein. Infectious microbes often have evolved strategies to avoid the immune system of the host. One example is CHIPS (Chemotaxis Inhibitory Protein of Staphylococcus aureus), which has a potent anti-inflammatory effect mediated by binding and blockade of the human C5a receptor. However, due to pre-existing anti-CHIPS antibodies, it cannot be safely and effectively used as an anti-inflammatory agent in the clinic. Therefore, the FIND® technology was used to remove B cell epitopes on CHIPS while preserving full biological activity. The FIND®-optimized CHIPS mutant, ADC-1004, demonstrates preserved C5aR binding and anti-inflammatory activity in vitro as well as therapeutic activity in animal models for reperfusion injury. Thus, ADC-1004 is a promising novel anti-inflammatory drug candidate.

For the pharmaceutical industry, success in the clinic should be the ultimate criterion for target validation. However the continued high rate of efficacy failures triggered in many pharmaceutical and biotechnology companies the need to develop a robust target validation strategy before moving molecular targets into drug discovery for a particular disease. Lorenz Mayr will discuss about Novartis’ comprehensive and contemporary framework of approaching target validation in drug discovery through: • Translating and establishing operational excellence from the target validation point of view to increase efficacy and profitability during drug discovery • Adopting multi layer approaches to discharge any unexpected challenges • Exploring new tools and gaining control on gene expression to successfully accomplish a multi disciplinary approach Personal Profile Lorenz Mayr studied biochemistry at the University of Tuebingen, molecular and cellular biology at the University of Colorado and received his diploma in biochemistry, organic chemistry and biophysics at the University of Bayreuth, where he also received his PhD in biochemistry and biophysics. He did his postdoctoral work with Prof Dr Peter S Kim at the Whitehead Institute for BioMedical Research at the Massachusetts Institute of Technology. In 1995, he joined the Central Research Department of Bayer AG where he worked for four years in various areas of technology development, external collaborations and assay development for high-throughput screening (HTS) in various disease areas. In 1999, he was nominated Project Leader at Bayer Pharma AG, Cardiovascular Research, with responsibility for target nomination, assay development and screening for the disease areas haematopoiesis and thrombosis. In 2001, he joined Novartis Pharma AG as a Technology Program Head for Novel Assay Technologies. Here he built up a process group dealing with industrialised aspects of modern lead discovery (cloning, protein expression, protein and peptide labelling, assay development, high-through¬put screening, hit-to-lead biology). Over the years, Lorenz has worked in a key role within several departments at Novartis. Since 2007, he is heading the Biology Unit of the Protease Platform, dealing with target validation, protein expression, assay development and compound profiling of all protease targets for drug discovery at Novartis Pharma AG/NIBR. He also works for several editorial and scientific advisory boards. Lorenz serves as a Member at the Board of Directors for the Society of Biomolecular Sciences.

Dr. Ming Wang is a Scientific Director in Metabolic Disorders Research at Amgen Inc.. He oversees multiple drug discovery programs in type 2 diabetes and cardiovascular disease. He is also involved in clinical development programs and licensing efforts in these disease areas. He led the research team that was responsible for the discovery and preclinical development of AMG 221, an anti-diabetic drug candidate that advanced to clinical trials. Prior to joining Amgen, Dr. Wang was a Research Advisor at Pharmacia where he built a New Target Discovery program in cardiovascular and metabolic diseases. Dr. Wang started his industry career at Parke-Davis/Pfizer, where he worked on mechanisms of actions of ResulinTM (troglitazone), NeurontinTM (gabapentin) and Gemcabene. During his tenure in Pfizer Global Research and Development, he served as the lead scientist in a cardiovascular drug discovery partnership with Xenon Genetics in Vancouver, Canada. Dr. Wang is a frequent speaker at scientific and drug discovery conferences and has over 40 publications. He is also a frequent reviewer for more than 10 scientific journals.

Dr. Grace has spent her entire career on biologics, specifically on cytokines, at Genentech, Millennium, AstraZeneca and Serono. Her PhD project was on biologics at The Walter and Eliza Hall Institute of Medical Research, Australia. Her post-doc projects were also on biologics with Dr. David Goeddel (who cloned and expressed human insulin, human growth hormone, tissue plasminogen activator, interferon-alpha and interferon-gamma etc) at Genentech. Dr. Grace continued working on biologics in a variety of diseases at Genentech, Millennium, AstraZeneca, Serono and ActoKine. Dr. Grace successfully shepherded basic research discoveries to product development at Genentech in 1993 and was appointed Head of Apoptosis Research at Millennium in 1996 for discovery of cytokine inducible drug resistance genes using functional genomics. Grace joined AstraZeneca as Section Head of Molecular Genetics for discovery of cytokine inducible genes in Alzheimer’s disease. At Serono, Grace was Director of Cytokine Genomics for discovery of novel cytokines in Women’s diseases. Her work with biologics have made her valuable to biotech and pharma, receiving also job offers from Glaxo, Biogen, Human Genome Sciences and Cell Therapeutics, in addition to the positions she was able to accept. Dr. Grace has been invited to present at 167 international conferences including the Nobel Symposium in Sweden in 1994. Grace received 13 scholarships and 5 Recognition Awards from Genentech. She published 89 papers and 27 patents (11 issued). Some of her publications (3 Nature, 1 Science, 3 Cell, 5 PNAS and 7 J. Immunol) have received 300-1000 citations. Grace founded ActoKine Therapeutics to discover new biologics for radioprotection and prevention of a board spectrum of viral infection (www.actokine.com). Grace also founded Student Vision (www.studentvision.org) and Nobel-Pauling (www.pauling.us, www.Nobel-Pauling.org) to inspire students of all ages in biotechnology.

Systems chemical biology and toxicogenomics are emergent areas that studies drug action across multiple scales of complexity, from molecular and cellular to tissue and organism levels. There is a critical need to develop network-based approaches to integrate the growing body of chemical biology knowledge with network biology, and to understand the relationship between drug action and genetic susceptibility to disease. Protein-protein interaction (PPI) networks is one approach which can be used to study the systemic properties and identify additional genes that may play major roles in modulating chemical response i.e. to drugs, environmental chemicals and xenobiotics in general. With the integration of other types of data such as diseases, it can improve our knowledge of disease-disease and contribute to the understanding of the underlying molecular mechanisms of drugs and how they might perturb biological pathways and generate side effects and adverse effects. Here, we will discuss how integration of large and diverse sources of information i.e. from molecular, cellular and phenotypic data associated to small molecules can lead to a generic disease chemical biology systems. Such systems will be illustrated through examples.

The economics of drug development place a premium on early and optimal assessment of a drug candidate’s safety, efficacy and deliverability. Comparative data on drugs already approved can play a key role in supporting pipeline decisions, but are often difficult to obtain. Only a small proportion of experimental data are published in peer-reviewed literature. FDA Drug Approval packages on the other hand are a particularly rich source of safety, efficacy and pharmacokinetics data. However, totalling more than 1.3 million pages, navigating these FDA documents can be particularly time-consuming. This session will highlight a new set of online tools which help unlock this resource to support key decisions in the drug development process.

Paul joined IDBS in 2005, bringing over 12 years experience in pharmacology, pharmaceutical drug development and ELN software development. Paul brings to IDBS scientific domain expertise as well as experience in the management of software development programs, having started his own software company in 2000 (Deffinity Solutions) which was purchased by IDBS in 2005. Prior to this, he was Senior Scientist at Sanofi-Synthelabo (now Sanofi-Aventis) for just under 5 years, where he managed a multidisciplinary department of scientists whose remit spanned target validation, primary efficacy testing and pharmacology, assay development, mechanism of action, cell biology and molecular biology. Paul obtained his PhD. in Computational Biology from Essex University in 1996, and has authored over 20 scientific papers and book chapters.