2nd Cytokines and Beyond Conference
Venue: Hilton Crystal City
|Event Date/Time: Apr 29, 2004||End Date/Time: Apr 30, 2004|
|Abstract Submission Date: Apr 15, 2004|
Day One: Thursday, April 29, 2004
8:15 Registration, Coffee & Breakfast Bakeries
9:15 Chairperson’s Opening Remarks
Alan Lewis, President, Celgene, San Diego
9:30 Company Showcases
For Sponsorship opportunities, please visit www.gtcbio.com or GTCBIO at firstname.lastname@example.org or (626) 256-6405
9:45 Keynote Address
Introducing Novel Cytokine-Like Endogenous Multifunctional Immune Alarmins (EMIAs)
Joost Oppenheim, Chief, Molecular Immunoregulation, NCI, NIH
Cytokines are pleiotropic regulatory peptides that interact with a wide variety of receptor expressing cells. Cytokines, like hormones, are endogenous intercellular signals but they function in host defense development and restoration of homeostasis. Despite the identification of hundreds of structurally distinct cytokines, they can be organized into distinct groups based on their utilization of members of seven families of structurally related receptors. However, I will introduce a number of endogenous molecular immune alarmins (EMIAs) that have non-cytokine functions, but interact with protein coupled receptors (GiPCR). They include antimicrobial á defensins, β defensins, which interact with CCR6 and one of which (mBD2) also activates TLR4 on immature dendritic antigen presenting cells (iDC). In addition, Eosinophil Derived Neurotoxin (EDN) a RNAse and High Mobility Group Box 1 (HMBG1), a nuclear binding factor use an identified GiPCR and TLR2 to mobilize and activate iDC. Furthermore, many autoantigens are also chemotactic in a GiPCR dependent manner for iDC and T cells. They include the myositis autoantigen histidyl tRNA synthetase which uses CCR5, while autoantigens involved in uvietis, IRBP and S-antigen, utilize CXCR5 and or CXCR3. These antimicrobial peptides and autoantigens can like many cytokines interact with iDC and influence innate and or adaptive immune responses.
10: 45 Networking, Refreshments, and Exhibiting
11:15 CCR12 and Other New Chemokine Receptors: Links Between Innate and Acquired Immunity and Targets for Therapy
Thomas J. Schall, Ph.D. President and CEO, ChemoCentryx
Immunity to pathogens links two effector arms of the immune response: the 'frontline' defenses of innate immunity with that of adaptive immunity. How this linkage occurs at the molecular level has been unclear: cells responsible for innate and adaptive immune cells are phenotypically discrete; agents reported to interact with both do so with low affinity. We investigated splice variants of chemokines that potently engage both 'classical' chemokine receptor CCR1 and a new receptor, CCR12, related to formyl peptide receptors and displayed on innate immune cells. Dissecting the mechanism of how an alternatively spliced chemokine engages both CCR1 and CCR12, we found the activity for CCR1 is contained in the 'body' of the protein, while the interaction with CCR12 is wholly contained in an exon-encoded peptide fragment. This peptide is the most potent attractant of monocytes and neutrophils tested, active in vivo, and generated by endogenous proteolysis. Thus we have identified a single protein that engages distinct chemokine receptors linking different cells in the orchestration of the immune response. The importance of CCR12 and other new chemokine receptors as disease targets will be examined.
11:45 Analysis of Cytokines and Chemokines in Rat Cecal Ligation and Puncture: A correlative analysis
Josef Heuer, Research Scientist, Eli Lilly and Company, Lilly Corporate Center, Indianapolis
Severe sepsis is a life threatening syndrome that typically results from an infection and exhibits both inflammatory and procoagulant involvement.. Sepsis afflicts nearly 750,000 patients annually with a high degree of mortality. Septic patients typically present and progress with heterogeneity of the septic condition resulting from a variety of factors and there is a need for reliable and practical measurements that can be applied to enable risk stratification of such patients. Although past animal studies sugested that immunomodulatory strategies would be beneficial in treating sepsis, results from clinical trials have not supported this hypothesis The purpose of our studies was to examine the role of cytokines and chemokines in a clinically relevant animal model of sepsis with respect to their associations with mortality, coagulation and organ damage. Polyethylene catheters were surgically implanted into the femoral vein and sepsis was induced by cecal ligation and puncture (CLP) under isoflurane anesthesia. A continuous infusion of 5% dextrose in 0.9 % saline was initiated immediately following surgery and blood samples were collected at 20 hrs. for analysis. Rats were monitored for survival out to 4 days. Blood samples were evaluated for blood glucose, bacteremia, plasma Protein C, D-dimer, hormones, chemokines and cytokines and the data was used in a multivariate analysis to determine relevant correlations with outcome. In addition, we have developed a hyperglycemic model of sepsis in CLP rats infused with total parenteral nutrition (TPN) and have examined the effects of hyperglycemia on the inflammatory response through analysis of cytokines and chemokines. The data from these studies suggest an important role for protein C, cytokines and chemokines in mediating coagulopathy and organ damage and in predicting outcome in severe sepsis.
12:15 Novel anti-TNF-alpha proteases for the treatment of inflammatory diseases
Ulrich Kettling, Chief Scientific Officer, DIREVO Biotech AG
TNF-alpha is an important target in the treatment of rheumatoid arthritis and other inflammatory diseases. Direvo has developed anti-inflammatory proteases that specifically inactivate human TNF-alpha by sequence-specific cleavage at defined positions. For this purpose, Direvo has employed its proprietary New Biological Entity (NBE) – Platform which allows the generation of novel proteases with tailor-made specificities and activities for nearly any pharmaceutical target protein. The NBE platform is particularly useful whenever there is no enzyme activity available from natural sources that can be used for optimization by protein engineering techniques. Therapeutic proteases possess several advantages over therapeutic antibodies. In comparison to antibodies which neutralize a target by binding and therefore exhibit only equimolar neutralization (one antigen – one antibody), therapeutic proteases irreversibly inactivate their target by proteolytic cleavage. This catalytic turnover leads to a several orders of magnitude higher efficacy compared to therapeutic antibodies or small molecule inhibitors. Studies with a first product candidate employing cell-based assays show encouraging results.
2:00 Anti-cytokine therapies for immune-mediated inflammatory disorders
Xiao-yu R. Song, M.D., Ph.D, Principal Research Scientist, Immunobiology Research , Research and Development, Centocor, Inc.
Abstract will be available soon.
2:30 Dominant-Negative TNF Antagonists: Inhibition of TNF Signaling Through a Novel Sequestration Mechanism
Paul M. Steed, Ph.D. Phone: 626-205-2777. Email: email@example.com
Tumor necrosis factor (TNF) promotes inflammation in rheumatoid arthritis and numerous other conditions. 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 were engineered that block TNF signaling via a novel sequestration mechanism whereby these proteins neither bind to nor stimulate signaling thorough TNF receptors, but retain the capacity interact with native TNF. Once variant:native heterotrimers are formed, the native TNF sequestered into them is rendered biologically inactive. The mechanism of these dominant negative molecules was verified by receptor binding assays, measurements of exchange with native TNF by native gel electrophoresis and ELISA analyses, and correlation with the antagonistic effects. Exchange with native TNF was found by several methodologies to be rapid both in vitro and in vivo and the PK and PD of these molecules were enhanced to improve efficacy. The novel DN mechanism allows for engineering of both ligand and receptor specificity, which is not attainable by the soluble receptor and antibody approaches. The selectivity of DN-TNFs were optimized with the goal to retain the anti-inflammatory functions of TNF while preserving effective response to infection. Such selective DN-TNFs have the expected efficacy profile but do not exhibit the profound affect innate immunity seen with the marketed pan-specific inhibitors.
3:00 Microencapsulated drug delivery potentiates pro-inflammatory cytokine inhibition
Carl Oettinger, Medical Director, Dialysis Clinic Inc
Pro-inflammatory cytokines constitute a major defense system to protect the organism from infectious agents and other immune insults. However, when these cytokines are released in excess, adverse local and systemic effects can occur. Pro-inflammatory cytokines are released by a variety of cells including macrophages, polymorphonuclear leukocytes, endothelial cells and dendritic cells. These cells are also phagocytic with macrophages producing in the greatest cytokine release. Albumin microcapsules, 1μ in size containing water soluble drugs are readily phagocytozed by macrophages and provide an improved method to deliver cytokine inhibiting drugs by direct cellular targeting. We have demonstrated marked improvement in the inhibition of TNF and IL1 using microencapsulated neutralizing antibodies to TNF and IL1, CNI-1493, clodronate, and antisense oligomers to TNF and NF-kB compared to equivalent doses of drug in solution. In-vitro and in-vivo models of endotoxic and septic shock in rats were evaluated. Microcapsules provide penetration to reticuloendothelial cells of solid organs and increased localization in areas of infection. Recent studies in our laboratory have found microencapsulated antisense to NF-kB to inhibit TNF, IL1, and IL6 in both in-vitro and in-vivo models. In addition, microencapsulated antisense oligomers to NF-kB have provided prolonged TNF, IL1, and IL6 suppression when given to primates with no adverse effects. Synergism in animal survival using microencapsulated antisense oligomers to NF-kB and CNI-1493, (drugs inhibiting the synthesis of TNF at different stages) has recently been demonstrated in a model of endotoxic shock. Microencapsulated drug delivery represents a technique to greatly improve the effectiveness of cytokine inhibiting drugs with potential to inhibit the inflammatory response in disease states such as sepsis and rheumatoid arthritis.
3:30 Networking, Refreshments, and Exhibiting
4:00 Significance of functional SNP’s in the IL-1 gene cluster
Leon M. Wilkins, Senior Director, Interleukin Genetics
Single nucleotide polymorphic (SNP) sites in the IL-1 gene cluster have recently been implicated as a factor in chronic inflammation and the risk for various diseases. We have determined the distribution of IL-1 haplotypes in multiple ethnic populations and have shown that specific haplotypes are associated with both inflammatory biomarkers and incidence of disease states. Our laboratory has focused on the identification of the set of specific SNPs that explain the biological activity of the different haplotypes, as they relate to disease states, such as cardiovascular disease. Molecular studies into the functionality of these inflammatory SNP’s have led us to findings in both the regulatory (promoter) region of the gene for IL-1 and protein structural differences in IL-1. Evidence points to genetic differences in both the quantity and quality of IL-1 gene expression that can influence both levels of IL-1 and the downstream activity of other inflammatory cytokines. A better understanding of the molecular events associated with the alleles of functional SNP’s and the interactions involved in haplotype patterns will help bridge the gap in understanding how these composite genotypes play a role in chronic inflammation and association to disease states.
4:30 Negative regulation of IL-6-type cytokine signaling
Peter C. Heinrich, Professor of Biochemistry and Chairman, Universitätsklinikum Aachen, Institut für Biochemie
The family of IL-6-type cytokines comprises interleukin (IL) -6, IL-11, leukemia inhibitory factor, oncostatin M (OSM), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine. These cytokines activate target genes involved in differentiation, proliferation, survival and apoptosis. They bind to plasma membrane receptor complexes containing the common signal transducing receptor chain gp130 and signal through the JAK/STAT and the MAP-kinase cascades. Recent studies on the molecular mechanism underlying IL-6 signal attenuation resulted in the identification of a phospho-Y-motif (Y759) of gp130 which recruits the tyrosine phosphatase SHP2 and the feedback inhibitor SOCS3. Both proteins act indepently on IL-6 signaling. Based on our observation that the D1-domain of gp130 is required for IL-6 binding and signaling and on the x-ray data on the hexameric IL-6 receptor complex from the group of Garcia we have generated a fusion protein consisting of the domains D1-D3 of gp130 fused by a 49 amino acids long linker to the domains D2 and D3 of the IL-6R-alpha. The fusion protein expressed in insect cells shows high affinity and specificity for IL-6 and is a promising new molecule for the "neutralization" of IL-6. The fusion protein strategy is presently applied to other IL-6-type cytokines.
5:00 Functional Validation of Novel Kinases Involved in Inflammation: Identification of an IKK-Related Kinase, IKKi
Helen Brady, Ph. D., Group Leader, Informatics and Functional Genomics, Celgene San Diego
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-êB regulated genes in response to mediators of inflammation. These effects appear to be independent of IêBá degradation and translocation of NFêB to the nucleus. Hence the data suggests that IKKi signals via a parallel but NF-êB 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.
5:30 Session Discussion
6:00 Cocktail Reception, Poster Session, and Exhibiting
Day Two: Friday, April 30, 2004
7:15 Registration, Breakfast, and Exhibiting
8:00 Chairperson’s Recap of Day One
Alan Lewis, President, Celgene, San Diego
8:10 Keynote Address
The Expanding Family of Class II Cytokines: New Biologic Agents for Clinical Use
Raymond P. Donnelly, Senior Investigator, FDA CDER
Several, novel, IL-10-related cytokines have recently been discovered. These include IL-22, IL-26, and the IFN- proteins: IFN-1 (IL-29), IFN-2 (IL-28A) and IFN-3 (IL-28B). The ligand-binding chains for IL-22, IL-26, and IFN- are distinct from that used by IL-10, however all of these cytokines employ a common second chain, IL-10R2 (CRF2-4), to assemble their active receptor complexes. Thus, IL-10R2 is a shared component in at least four distinct class II cytokine receptor complexes. IL-10 initially binds to IL-10R1; IL-22 binds to IL-22R1; IL-26 binds to IL-20R1, and IFN- binds to IFN-R1 (also known as IL-28R). The IL-10R2 chain is then recruited to the intermediate complexes formed by the binding of ligand to these receptors. This in turn activates a signal transduction cascade that results in rapid activation of several transcription factors, particularly STAT1 and STAT3. Activation by IL-10, IL-22, IL-26 or IFN- can be blocked with neutralizing antibodies to the IL-10R2 chain. Although IL-10R2 is broadly expressed on a wide variety of tissues, only a subset of these tissues express the ligand-binding chains. The receptors for these cytokines are often present on cell lines derived from various tumors, including liver, colorectal and pancreatic carcinomas. Consequently, the receptors for these cytokines may provide novel targets for inhibiting the growth of certain types of cancer. In addition, the IFN- proteins possess anti-viral activity, and may be useful in treating certain types of viral infection.
9:00 Use of TGFγβ Anatagonists for the Treatment of Pathologic Fibrosis
Steve Ledbetter, Vice President, Genzyme
Transforming growth factor beta is a multifunctional cytokine that orchestrates diverse biologic processes for the successful repair of damaged tissues and organs. TGFâ also has profibrogenic properties that are implicated in the progressive loss of function associated with many chronic diseases and, in these settings, antagonism of TGFâ may have therapeutic benefit. For this reason we examined a murine pan-neutralizing monoclonal antibody against TGFâ in preclinical models of chronic renal disease. We show that neutralization of TGFâ is anti-hypertensive, restores physiologic production of NO, reduces tissue hypoxia and reduces collagen production while increasing matix degradation. Preservation of tissue function was accompanied by morphologic improvement. Genzyme and Cambridge Antibody Technology have collaborated to identify a human monoclonal antibody that binds and antagonizes the biologic activity of all three isoforms of TGFâ. This antibody has biologic activity analagous to the murine neutralizing antibody and is proposed for clinical testing.
9:30 IL-17 and airway diseases
Alexandre Trifilieff, Research Scientist, Head, Laboratory of Pharmacology, Novartis
The recent sequencing of the human genome has led to the identification of at least six IL-17-related cytokines that share 20-50% homology to the founder of this family IL-17A. They have been named IL-17A-F. The biological action of the IL-17s is pro-inflammatory and partially overlaps, although the observed difference in their expression pattern might suggest distinct biological roles. Among this family, IL-17A and IL-17E (IL-25) are currently the best characterised. In animal models, IL-17A indirectly recruits neutrophils into the airways via the release of inflammatory mediators (IL-8, GRO-alpha). In contrast, IL-17E promotes eosinophilia and Th2 cytokines release. Taken together, these studies suggest that IL17A may be an attractive target for neutrophilic airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. Whereas, inhibition of the biological activity of IL-17E could provide a novel therapeutic approach for treatment of allergic respiratory disease such as asthma.
10:00 The Role of Interleukin-9 (IL-9) in Airway Hyperresponsiveness: Potential Therapeutic Applications of Anti-IL-9 mAbs
Peter Kiener, Vice President, Medimmune
Several TH-2 cytokines have been implicated in airway diseases like asthma. In humans Interleukin-9 (IL-9) has been genetically linked to asthma, and expression of IL-9 and its receptor are found elevated in lung tissue of severe asthmatics. In IL-9 has been associated with eosinophilia, IgE production, epithelial hypertrophy, mucin production, and airway hyperresponsiveness (AHR) in experimental models of asthma. However, the characterization of the role of individual cytokines in the regulation of AHR is unclear due to the complexity of the inflammatory infiltrates and the functional redundancy of immune cells in these diseases. We have observed that mice that systemically overexpress IL-9 were highly sensitive to MCh challenge compared with their strain-matched controls. This occurred in the transgenic animals in the absence of epithelial hypertrophy, mucin production, or complex inflammatory infiltrates. In addition, in these IL-9 transgenic mice, epithelial-localized mast cells were observed in tracheal tissue and the serum levels of murine mast cell protease 1 were elevated. In a variety of strains of mice, administration of IL-9 intranasally boosted AHR and increased levels of mMCP-1 in serum. Furthermore, administration of a neutralizing anti-IL-9 mAb to normal mice (to block endogenous IL-9) reduced responsiveness to subsequent MCh challenge. However in mice whose mast cell numbers are attenuated (mice carrying the KitW-v mutation) the local administration of IL-9 did not give rise to any significant increases in AHR. Our results suggest that IL-9 can directly influence AHR, likely in part through the regulation, recruitment of, and/or activation of mast cells. Development of a humanized, affinity-enhanced anti-human IL-9 mAb will be briefly discussed.
10:30 Networking, Refreshments, and Exhibiting
11:00 IL-13: a key regulator of airway epithelial secretion
Henry Danahay, Research Scientist, Novartis
IL-13 has been implicated as a key regulator of allergic disease. Animal studies have indicated that in the airways, IL-13 plays a central role in the development of an eosinophil-rich inflammation, subepithelial fibrosis, increased collagen deposition, smooth muscle thickening, airway hyper-responsiveness and an increase in the density of mucin secreting goblet cells in the surface epithelium. Using well differentiated cultures of human bronchial epithelial cells (HBEs) we have recently demonstrated that IL-13 (& IL-4) can regulate goblet cell density through a direct interaction with the epithelial cells. The increase in epithelial mucin load is at least partially mediated through an increase in MUC5AC production, and is sensitive to inhibitors of the MAP kinase and PI3 kinase signalling pathways. In tandem with the increase in mucin load, IL-13 also switches the epithelium from its normal fluid absorptive function to a fluid hypersecretory phenotype. IL-13 achieves this through a combination of effects targeting both apical and basolateral ion conductances. The combination of the increased mucin and fluid secreting capacities of the human airway epithelium indicate a well balanced process whereby the lung can ensure appropriate hydration of secreted mucins. This plasticity in the system is important to avoid the catastrophic consequences of inadequate Cl- secretion that are central to the development of cystic fibrosis. Evidence is now emerging of a potential role for IL-13 in additional respiratory diseases including chronic bronchitis. IL-13 directed therapies therefore represent novel approaches to diseases associated with the over-production of mucus.
11:30 Neuro-immune interactions during intestinal inflammation
Michel Neunlist, Senior Scientist, INSERM U539, Nantes, France
Intestinal inflammation during chronic or infectious disease is associated with fonctional disturbances (secretory and motility disturbances; pain) that are in part mediated by the enteric nervous system (ENS). Recent data suggest that inflammatory mediators (cytokines, prostaglandins) acting on enteric neurons could be responsible for these symptoms. Furthermore, inflammatory mediators can also modify the neurochemical phenotype of enteric neurons and could therefore be responsible for long term alterations in gut functions. Such a mechanism could be involved in post-infectious irritable bowel syndrome. In addition, besides being a target for inflammatory mediators, components of the ENS (neurons or enteric glial cells) can modulate intestinal inflammation by either directly secreting cytokines or modulating cytokines secretion by immune cells. We will especially focus on the effects of cytokines on properties of enteric neurons (gene expression and electrophysiological properties) and on the imunomodulatory role of the ENS and of enteric neuromediators.
12:00 Mechanistic Insights Into Strategies for Targeting Cytokine Receptors
Adrian Whitty, Ph.D., Associate Director, Biogen Idec, Inc.
Achieving a quantitative understanding of the activation mechanism of a cytokine receptor can lead to unique insights into how best to target it with protein or small molecule antagonists or agonists. I will illustrate this idea using specific examples drawn from our own work on the Interleukin-4 Receptor and other cytokine receptors and from the work of others, focusing in particular on the importance of understanding the interactions that occur between a receptor’s component molecules on the cell surface. I will highlight some specific pieces of mechanistic information that are relevant to drug development, describe some simple experimental approaches for obtaining this information, and will discuss how the information can be used to suggest specific strategies for drug discovery or design.
2:00 IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: Comparative evaluation of IL-2, IL-15 and IL-21
Chris Clegg, Sr. Director, ZymoGenetics
Cytokines that utilize the common-receptor gamma-chain for regulating CD8+ T cell responses to antigen include IL-2, IL-15 and the recently identified IL-21. The ability of these cytokines to regulate anti-tumor activity in mice has generated considerable interest in understanding their mode of action. Here, we compare the ability of IL-2, IL-15 and IL-21, to stimulate immunity against tumors in a syngeneic thymoma model. Durable cures were only achieved in IL-21 treated mice. By monitoring both endogenous and adoptively transferred tumor-specific CD8+ T cells, it was determined that IL-21 activities overlap with IL-2 and IL-15. Similar to IL-2, IL-21 enhanced antigen activation and clonal expansion. However, unlike IL-2 treatment, which induces activation-induced cell death, IL-21 sustained CD8+ T cell numbers long-term as a result of increased survival, an effect often attributed to IL-15. These findings indicate that the mechanisms utilized by IL-21 to promote CD8+ T cell responses offer unique opportunities for its use in malignant diseases and infections.
2:30 CEL-1000 Prophylaxis in HSV and Malaria Murine Models of Human Disease: The Central Role and Timing of Interferon Gamma*
Daniel H. Zimmerman, Senior Vice President, Cel-Sci Cor.
CEL-1000 is a small peptide with immunoregulatory activity as demonstrated in two different murine models of human disease: 1) malaria, caused by a parasite and; 2) viral skin lesions, which can progress to zosteriform spread and be fatal, caused by herpes simplex virus. CEL-1000 is derived from a region of the second domain of the beta chain of MHC class II molecule, a conserved region between mice and man, involved in the regulation of immune responses. In the malaria model, using monoclonal antibody ablation/depletion experiments, we have shown that CD4+ cells and IFN- but not CD8+, NK cells or IL-12 are required for activity in the action phase. This is consistent with elevated IFN-in the sera and CD4+ IFN-+ cells in the liver, the prime site of the parasite infection at this stage. In the HSV model we demonstrated a requirement by CEL-1000 for CD4+ cells and IFN- at both the induction and action phases. Interestingly, in the induction phase for both models, IFN- is not detected in sera of CEL-1000 treated mice by ELISA (malaria model) or RayBiotech membrane protein-array (HSV model) assays. However, IL-12 is detected, as well as several other pro- inflammatory chemokines and cytokines in the sera by the membrane protein array, peaking within the first day and decaying at different rates in the following five days with IL-12 being the most sustained. CEL-1000 can be considered a Th1 modulator based upon the importance of Interferon- (IFN-and CD4+ cells responses for protection with both of these diseases in the mouse. Preliminary experiments to be presented elsewhere on isolated cells support these observations. We believe that CEL-1000 will be effective in man.
*This work was supported in part by NIH grants AI1R43055069-01 and U-01 AI054747-01 and a CRADA, NCRADA NMRC-96-NMR-500, with NMRC.
3:00 A new generation of therapeutic proteins based on an original approach of natural genetic variability
Jean-Louis Escary, President & CEO, Genodyssee
GenOdyssee (GO) is developing a series of compounds based on exploiting genetic mutations that confer super-therapeutic status on naturally produced cytokines. GO is developing therapeutics based on the assumption that genetic mutations can confer natural superiority to the pharmacological profiles of corresponding host human genes, such as the genes that encode for blockbuster therapeutic cytokines such as IFN-alpha and EPO. The company has programs in virology and oncology. The lead virology candidate, GEA007.1, is a natural variant of human IFN-alpha that has demonstrated in vitro up to 100x higher antiviral activity than marketed IFN alpha 2a or 2b for hepatitis treatment. The lead oncology candidate is GEA009.2, another variant of human IFN-alpha, that has demonstrated, in vitro & in vivo, stronger immune system stimulatory activity with less accompanying toxicity than currently marketed IFN 2b for cancer treatment. The discovery of natural genetic mutations in the human population that confer superiority to therapeutic proteins appears to be unique in the industry and the sole property of GO. The company has filed 31 patent applications in the United States , the European Community, and Japan . At this time, the patents protecting the IFN-alpha and EPO variants, and the innovative biologics discovery concept of GO have been awarded in France .
3:30 Small molecule approach to blocking Cytokines
Alan Lewis, President, Celgene
Tremendous progress has been made developing cytokine modulators that are antibody- or receptor-based. With the success of drugs such as Infliximab, Enbrel, Humira and Kineret, attention has been placed on a new generation of small molecule drugs that control cytokine release and/or production. Progress in the development of several of these approaches will be reviewed and will include targeting of NFêB, MAP kinases, PDE4 as well as several novel immunomodulator drugs under development for immune-inflammatory diseases and cancer.
4:00 Conference concludes