Stratecgic Research Institute, Baltimore, MD
March 8-10, 2004
Tuesday, March 9, 2004
7:15 - 8:30 - Registration, Networking & Exhibits
8:30 - 8:40 - Chairpersons’ Opening Remarks
Martin Braddock, Ph.D.
Associate Director, Respiratory & Inflammation Research Area
Alan Lewis, Ph.D.
CELGENE SAN DIEGO
8:40 - 9:15 - KEYNOTE ADDRESS: Peripheral Blood Leukocyte Gene Expression Profiling: Therapeutic and Biomarker Application
Steven B. Abramson, M.D.
Chairman, Dept. of Rheumatology - Hospital for Joint Diseases
NYU SCHOOL OF MEDICINE
9:15 - 9:45 - KEYNOTE ADDRESS: New Molecular Mechanisms for the Anti-Inflammatory Effects of Glucocorticoids
Glucocorticoids are the most effective anti-inflammatory therapies and work in several ways, including activation of anti-inflammatory genes (such as SLPI, MKP-1), switching off inflammatory genes and post-transcriptional modification of inflammatory proteins, such as cytokines. Switching off many inflammatory genes can be explained by recruitment of histone deactylases (predominantly HDAC2) to inflammatory genes activated by proinflammatory transcription factors, such as NF-êB. In the case of GATA-3 corticosteroids may also interfere with its nuclear localization to prevent activation of Th2 cytokine genes.
Peter J. Barnes, Ph.D.
Professor, National Heart & Lung Institute
IMPERIAL COLLEGE LONDON
9:45 - 10:15 - KEYNOTE ADDRESS: Steroid Insensitivity in Severe Asthma and COPD
Glucocorticoids are very effective anti-inflammatory therapies but are ineffective in severe asthma and COPD. Steroid sensitivity in severe asthma depends predominantly on GR nuclear translocation and GR phosphorylation status. Oxidative stress, found in high levels in COPD, can also affect GR function by targeting either GR nuclear translocation or co-factor activity. Drugs that affect GR nuclear translocation and/or co-factor activity may restore steroid sensitivity in these subjects.
Ian Adcock, Ph.D.
Translational Research, Group, Thoracic Medicine
IMPERIAL COLLEGE LONDON
10:15 - 10:55 - Refreshments, Networking & Exhibits
10:55 - 11:25 - KEYNOTE ADDRESS: Regulation of Progressive Fibrosis
Studies with fibrotic tissues and fibroblasts indicate TGFb and associated receptors and signaling pathways are critical for initiation of acute fibrogenesis and mediate conversion to chronic progressive fibrosis. Drug inhibition of TGFb receptors, or using a Smad3 null mouse, blocks the process of fibrogenesis. TGFb and downstream genes involved in matrix metabolism regulate altered pro-fibrotic microenvironments and induce progressive fibrogenesis, defining multiple targets for therapeutic intervention.
Jack Gauldie Ph.D., FRSC
Professor & Chairman, Dept. of Pathology & Molecular Medicine
11:25 - 11:55 - KEYNOTE ADDRESS: Utility of Cytokine Targets in Inflammatory Synovitis
A consequence of elucidating components of the inflammatory response in inflammatory synovitis in rheumatoid and psoriatic arthritis has been the evolution of cytokine targeting agents (eg infliximab, etanercept) that provide impressive clinical benefits in a subset of patients. Significant challenges now concern identification of novel targets beyond TNFa and IL-1 that can offer similar or even greater benefits in both partial and non responding clinical subgroups. We have studied the inflammatory effects of the innate response cytokines IL-15 and IL-18 in the context of inflammatory synovitis. Such studies have demonstrated pro-inflammatory effects of both cytokines in synergy in vitro in synovial culture systems and in vivo in animal models of arthritis. More recently clinical proof of concept studies have provided encouraging early results. This presentation will review some of these data and explore the rationale for targeting cytokines encompassing innate to acquired immune regulation in complex autoimmune disorders. Finally the potential for multiple targeting will be discussed.
Iain B. McInnes, MRCP, Ph.D.
Professor of Experimental Medicine
Honorary Consultant Rheumatologist
CENTRE FOR RHEUMATIC DISEASES, GLASGOW ROYAL INFIRMARY
11:55 - 12:25 - KEYNOTE ADDRESS: Investigating Immune Responses Directly In Vivo
Using novel animal models combined with the latest techniques in imaging, microscopy and cytometry will enable us to characterise the location and kinetics of the critical cellular and molecular interactions underlying diseases such as allergic asthma and rheumatoid arthritis under physiological conditions, in vivo, in real time. Enhanced understanding of how such immune responses are initiated, maintained and regulated in peripheral tissues and lymphoid organs and how these sites communicate with each other will facilitate the rational design of therapeutic interventions.
Paul Garside, Ph.D.
Professor of Immunobiology, Infection & Inflammation
UNIVERSITY OF GLASGOW
12:25 - 1:45 - Luncheon
1:45 - 2:15 - The Influence of TNF-a Gene Polymorphisms on Experimental and Clinical Pain Responses in Humans
Tumor necrosis factor (TNF) is associated with many chronic inflammatory conditions, but the relationship between polymorphisms of TNF and its effect on acute pain has not been clearly elucidated. In this study, we examined the influence of common genetic polymorphisms of TNF genes on the modulation of clinically and experimentally induced acute pain in humans. Subjects (N=560) rated sensory intensity and unpleasantness for heat stimuli and 3 min cold pressor test; a subset of 121 patients underwent oral surgery. Maximum postoperative pain was recorded after local anesthetic offset by visual analog scale and evaluated over 60 min post-NSAID analgesic (ketorolac 15 mg IV). In the present human cohort, 7 TNF single nucleotide polymorphisms (SNPs) did not demonstrate any significant association with clinically or experimentally induced pain responses or on NSAID analgesia. Although none of the SNPs evaluated showed an association with pain responses for this cohort, this may not be representative of individual responses, the effect of other TNF polymorphisms, or other acute pain conditions.
Christine Picco, BA
Postbaccalaureate Research Fellow
NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
2:15 - 2:45 - Dominant-Negative TNF Antagonists: Inhibition of TNF Signaling Through a Novel Sequestration Mechanism
Tumor necrosis factor (TNF) promotes inflammation in rheumatoid arthritis, Crohn’s disease, osteoporosis, type 2 diabetes and multiple sclerosis. Several anti-TNF therapies, based on soluble decoy receptors and monoclonal antibodies, have proven efficacious in human inflammatory diseases. Using a rational, structure-based computational strategy, we designed TNF variants that block TNF signaling via a novel sequestration mechanism. Protein Design Automation® (PDA®) technology was used to engineer variant TNF proteins that neither bind to nor stimulate signaling thorough TNF receptors R1or R2, but retain the capacity to rapidly form heterotrimers with native TNF. Once variant:native heterotrimers are formed, the native TNF sequestered into them is rendered biologically inactive, as demonstrated by a lack of ability to induce caspase activity and NFkB-dependent transcription in several cell lines.
Jonathan Zalevsky, Ph.D.
Associate Director, Inflammation
2:45 - 3:15 - Anti-Inflammatory Proteases Inactivates TNF-Alpha
Direvo has developed an anti-inflammatory protease that specifically inactivates TNF-alpha by sequence-specific cleavage at a defined position. Therefore Direvo has employed its proprietary New Biological Entity (NBE) – Platform which allows the generation of novel proteases with required specificities and activities for nearly any proteogenic pharmaceutical target. Preclinical studies with a first product candidate started end of 2003.
Ulrich Kettling, Ph.D.
DIREVO BIOTECH AG
3:15 - 4:00 - Refreshments, Networking & Exhibits
4:00 - 4:30 - Interleukin-1b as a Therapeutic Target: Opportunities for Inflammatory Disease
Interleukin-I (IL-1) is a pivotal mediator of inflammation and tissue damage in multiple organs in both animal models and in man. The pro-inflammatory nature of IL-1 may make it an attractive target for therapeutic intervention in a number of diseases in man which include rheumatoid and osteoarthritis, inflammatory bowel disease and inflammatory diseases of the lung and central nervous system. In this presentation, the role of IL-1, the IL-1 pathway and possible therapeutic antagonist approaches directed against IL-1 will be discussed, together with an appraisal of the efficacy of the IL-1 receptor antagonist, Anakinra and Pralnacasan in rheumatoid arthritis in man.
Martin Braddock, Ph.D.
Associate Director, Respiratory & Inflammation Research Area
4:30 - 5:00 - Therapeutic Potential of CCR2 Antagonism for Chronic Inflammatory Diseases
CCR2, a critical receptor on monocytes, facilitates monocyte migration into sites of inflammation. Data from knockout mice indicates this receptor may be a point of therapeutic intervention for chronic inflammatory diseases. While a number of small molecule inhibitors of CCR2 have been described, there have been no reports of in vivo pharmacological effects. In this presentation, we describe pharmacological and immunological effects of CCR2 antagonists in rodent models of inflammation.
Carrie Brodmerkel, Ph.D.
Senior Research Scientist
5:00 - 6:30 - Networking Reception
Wednesday, March 10, 2004
7:30 - 8:30 - Breakfast, Networking & Exhibits
8:30 - 8:35 - Chairs’ Recap
8:35 - 9:05 - Anti-Inflammatory Effects of a Small-Molecule Dual Inhibitor of the Leukocyte Proteases Cathepsin G and Chymase
Serine proteases from neutrophils, such as cathepsin G, elastase, and proteinase 3, and from mast cells, such as chymase and tryptase, degrade extracellular matrix and induce additional leukocyte migration. We have focused attention on cathepsin G (Cat G) and chymase which are two chymotrypsin-like enzymes implicated in pathological inflammatory conditions. Although Cat G and chymase cleave various matrix components, chymase also induces the formation of pro-inflammatory cytokines and chemokines, which then stimulate the infiltration of more inflammatory cells as part of a chronic condition. Herein, we describe a novel, nonpeptide, small-molecule inhibitor of both Cat G and chymase along with its pharmacological efficacy in animal models of inflammation.
Lawrence de Garavilla, M.S., Ph.D.
Research Fellow, Drug Discovery
JOHNSON & JOHNSON PHARMACEUTICAL R&D, L.L.C.
9:05 - 9:35 - Development of Novel Natural Product Derived NF-kB and Proteasome Inhibitors
Michael A. Palladino, Jr., Ph.D.
VP of Technology & Scientific Co-Founder
9:35 - 10:05 - Functional Validation of Novel Kinases Involved in Inflammation: Identification of a IKK-Related Kinases, IKKi
We have taken a functional genomics approach to identify novel kinases induced in inflammatory paradigms. IKKi was identified as a TNF-alpha inducible kinase in endothelial cells. It appears to play an important role in modulating a subset of NF-kB regulated genes in response to mediators of inflammation. These effects appear to be independent of IkBa degradation and translocation of NFkB to the nucleus. Hence the data suggests that IKKi signals via a parallel but NF-kB independent pathway. We have identified several potential alternative pathways that may be involved in regulating this subset of genes including C/EBP delta and IRF3.
Sabita Sankar, Ph.D.
Senior Scientist I, Cell Signaling and Target Discovery
CELGENE SAN DIEGO
10:05 - 10:50 - Refreshments, Networking & Exhibits
10:50 - 11:20 - Pharmacology of Nuvion, A Humanized Anti-CD3 Monoclonal Antibody
Nuvion (Visilizumab), a humanized, non-FcR binding IgG2 anti-CD3 monoclonal antibody, is currently under evaluation for the treatment of steroid refractory ulcerative colitis (UC). The mechanism of action of Nuvion may include the selective apoptosis of activated T cells, partial TCR signaling, generation of regulatory T cells, shift to Th2 phenotype, alteration of T cell trafficking, and other pathways. Pharmacodynamic effects of Nuvion will be discussed.
Vladimir S. Vexler, Ph.D.
PROTEIN DESIGN LABS
11:20 - 11:50 - Modulation of Redox-Sensitive Inflammatory Pathways for the Treatment of Inflammatory Diseases: The Discovery and Development of Vascular Protectants
Oxidative stress plays an important role in the pathophysiology of many chronic inflammatory diseases including atherosclerosis, arthritis and asthma. It is well known that oxidant signals generated in the vasculature mediate the inducible expression of several inflammatory genes such as VCAM-1 and MCP-1 that are sensitive to modulation through control of intracellular redox homoestasis. By targeting these redox-sensitive inflammatory genes, AtheroGenics has identified a series of novel, small molecular weight and orally-deliverable therapeutics, termed vascular-protectants, for the treatment of chronic inflammation. These innovative new therapies demonstrate preclinical efficacy in animal models of arthritis, atherosclerosis, organ transplant rejection, and asthma. Furthermore, clinical studies have proven these compounds to be safe, well-tolerated and efficacious. Preclinical data and positive Phase II clinical results from the Canadian Antioxidant Restenosis Trial-1 (CART-1) with AGI-1067, the company’s lead drug candidate for the treatment of atherosclerosis and restenosis, will be discussed.
Charles Kunsch, Ph.D.
Senior Director, Biological Research
11:50 - 12:20 - Testing Experimental Compounds in Their Animal Models of Acute and Chronic Inflammation
A confidentiality disclosure agreement must be signed. Ideally, the client should be familiar with the fundamentals (methods and techniques) of the procedures that are used to induce acute and chronic inflammation in the animal such as rat carrageenan air pouch and rat adjuvant arthritis models. The client should have knowledge of what parameters are used (e.g. paw edema, fibrinogen levels, histopathological changes) to measure the efficacy of a compound and what is an appropriate standard drug to be used for comparison. Statistics and presentation of data are important parts of the report as well as the design of the study. All of these should be discussed thoroughly before the study begins. Finally, presenting a time line for the experiment, and where to ship biological samples for analysis are important items to be discussed prior to the start of study.
Richard P. Carlson, Ph.D.
Director of Inflammation Research
PROVIDENT PRECLINICAL INC.
12:20 - 1:45 - Luncheon
1:45 - 2:15 - Micromethason for the Treatment of Inflammation Diseases
Successful and safe delivery of small molecule drugs, RNA transcripts or even oligonucleotides to inflammation sites still remains a major challenge in the drug delivery industry. The novosom AG, Germany, presents novel, simple and pharmaceutically highly acceptable liposomal delivery systems. Micromethason by novosom AG is a liposomal dosage form of soluble Dexamethasone with superior activity at very low amounts of drug. When administered systemically, Micromethason effectively targets the inflamed sites and treats inflammation for weeks in a rat model of antigen induced arthritis. Therapeutic treatment with the liposomal glucocorticoids resulted in a complete remission of inflammation. Bone and cartilage were nearly unaffected and the joints appeared to be complete cured. Novosom also represent the Smarticles®-technology that facilitate the delivery of nucleic acids with comparable efficiency via the same delivery route.
2:15 - 2:45 - Membrane-Anchored Lipid Conjugates: Novel Multi-Functional Anti-Inflammatory Drugs
The control of inflammatory mediators, produced from cell membrane phospholipids by phospholipase A2 (PLA2), is a prevalent therapeutic target. Enrichment of cell-surface glucosaminoglycans (GAG) is desirable for cell protection, as their stripping exposes the cell to inflammatory mediators. To address both needs, we linked GAG to membrane-anchored PLA2-inhibiting phospholipids. These lipid-conjugates, given to animals by diverse routes, ameliorated sepsis, IBD, encephalopyelitis (EAE) and asthma. These multi-functional anti-inflammatory drugs (MFAID) introduce a novel strategy for the treatment of inflammatory/allergic diseases.
Saul Yedgar, Ph.D.
Walter and Greta Stiel Chair in Heart Studies
Department of Biochemistry
HADASSAH MEDICAL SCHOOL