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Immunology is all about balance in the immune system. At Novimmune, we seek to tip the balance in favour of health. Immunological diseases encompass a wide variety of disorders, affecting a steadily increasing proportion of people in modern society. Immunological diseases include inflammatory bowel disorders, diabetes, asthma and chronic lung disease, chronic arthritis, atherosclerosis, chronic degenerative brain disorders, lupus and cancer. During the past decade, dramatic advances have been made in understanding the mechanisms regulating the immune system, its pathological processes and the processes of immune deviation. As such, it is now recognized that systemic or organ-specific inflammatory, infectious and autoimmune conditions share basic mechanisms of initiation, maintenance and progression. By exploiting this knowledge, Novimmune is working to develop treatments satisfying the, largely unmet, needs of patients affected by the many diseases within the inflammatory disease spectrum. During early development we will work to understand the benefit risk of our new drug candidates, to maximize value and justify continued investment in the disease arena selected. In the later phase of development we will focus on operationally efficient and cost effective confirmatory trials ensuring our products will be supported by relevant data enabling their safe and effective use in medical practice worldwide. Diabetes is now known to be the end result of an inflammatory process affecting the beta cells of the pancreas. In early diabetes, this process is thought to be initiated and propagated by the effect of Th1-secreted cytokines [e.g. interferon (IFN)] and suppressed by Th2-secreted anti-inflammatory cytokines [e.g. interleukin(IL)-4, IL-10]. This led to the hypothesis that diabetes can be prevented using Th2-secreted cytokines. This hypothesis was examined in various animal models. All these interventions prevented diabetes, either by a direct effect of the anti-inflammatory cytokines or via their stimulatory and inhibitory effects on Th2 and Th1 cells, respectively[1]. Another approach that can skew the cytokine cascade from a Th1 to a Th2 response is the use of a non-depleting anti-CD3 antibody. A novel anti-CD3 monoclonal antibody has been shown to induce IL-4 and IL-10-producing Th2 cells while suppressing IFN-producing Th1 cells. Treatment of NOD mice with this antibody prevents or reverses diabetes. On the basis of these observations, a randomized controlled trial in patients with new-onset type 1 diabetes was initiated, results of which demonstrated a preserved C peptide response and reduced requirement for exogenous insulin[2,3,4]. In 2009, Novimmune will initiate a phase II-III program exploring the effect of NI 0401, a fully human anti CD3 antibody with an improved dosing regimen relative to other MAbs in current development, in patients with Type 1 Diabetes. Inflammatory bowel disease (IBD) is a chronic inflammation of the intestines that can cause diarrhea, bleeding, abdominal pain, fever, joint pain and weight loss. It is estimated that, in the US alone, over one million individuals have IBD and the number of patients diagnosed with the condition is increasing each year. Genetic and environmental factors play a role in the disease process. Two main disease entities, Crohn's Disease and Ulcerative Colitis are the most common inflammatory bowel disorders. Although these conditions share common symptoms and are often misdiagnosed for each other, each disease affects the digestive tract differently and requires unique treatment. Crohn's Disease is a chronic inflammatory disease of the gastrointestinal tract thought to be a result of the stimulation of a dysfunctional immune response in genetically susceptible individuals. The resultant intestinal mucosal inflammation involves all layers of the intestinal wall, frequently leading to debilitating intestinal symptoms as well as the development of serious complications including intestinal perforation, abscess formation, bowel obstruction and fistula formation leading to severe impairment of the quality of life. Approximately 80% of patients will require surgery within the first 15 years of diagnosis, but surgical resection is not curative and patients experience relapses of varying severity throughout life[5-10]. While introduction of biologic therapy led to significant improvements in disease management, primary and secondary treatment failure, as well as contraindications and treatment limiting side effects, leaves many patients requiring alternative therapy. Therefore, new agents which can support treatment free maintenance of clinical remission, reducing complications, hospitalizations, surgery and disease associated mortality, would significantly improve the treatment of this condition[11]. In health, the intestinal mucosa is exposed to a large number of commensal bacteria and food antigens. Regulatory T lymphocytes (Tregs) are thought to play a critical role in limiting inflammation in response to these nonpathogenic antigens, and defects in this T-cell subset have been implicated in the pathogenesis of IBD. In addition to the T cell transfer model of colitis, multiple murine models have demonstrated a crucial role for Tregs in the control of intestinal inflammation and elucidate the mechanisms of their generation, migration, interactions and function[12-17]. A number of pharmacologic agents have been shown to promote Treg number or function and may be of benefit for the treatment of IBD. One of the best characterized is anti-CD3 monoclonal antibody. Although anti-CD3 exerts some of its effects by deletion or induction of anergy in pathogenic T cells, anti-CD3 therapy has been shown to promote the development of adaptive TGF-ß-producing Tregs in a murine model of diabetes, lead to the accumulation of IL-10-expressing FoxP3- (Tr1) cells in the small intestine and IL-10-expressing FoxP3+ T cells in the lamina propria of the colon and result in the production of TGF-ß which may be responsible for the observed generation of Tregs following therapy[18]. Novimmune has completed a preliminary clinical trial with NI0401 in patients with Crohns disease, over 80% of whom had failed prior treatment with at least one anti TNF agent. Results of this study demonstrated a significant treatment effect on endoscopic response markers and mucosal healing which may result in prolongation of disease remission. This concept is being tested in a further study currently in progress.
Acute and Chronic Inflammatory Lung Disorders Inflammation in the lung can cause a variety of respiratory disorders leading to acute or chronic inflammatory lung disease. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by local and intense inflammatory responses, with accumulation of several cell types and soluble mediators in lung epithelium. There are parallel anti-inflammatory response and lung remodeling, with deposition of collagen leading to chronic lung fibrosis[19]. Asthma is a complex inflammatory disease of the lung characterized by airway hyper-responsiveness (AHR), eosinophilic inflammation, mucus hypersecretion and subepithelial fibrosis. Although multifactorial in origin, the inflammatory process is believed to be a result of inappropriate immune responses to common aeroallergens in genetically susceptible individuals. The initial clinical presentation varies, most often with intermittent symptoms but sometimes with constant wheezing, cough, or shortness of breath. Wheezing on expiration is the classic symptom. Symptoms typically increase with exposure to allergens and triggers, such as viral upper respiratory infections, pollen, dust mites, animal dander and environmental irritants (most commonly tobacco smoke).In some cases, asthma symptoms diminish after childhood[20-22] . Chronic Obstructive Pulmonary Disease (COPD) is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. COPD is essentially unknown in children and is rare in younger adults without a history of alpha1-antitrypsin deficiency. After age 40, however, the prevalence of COPD increases substantially with aging. In general, risk for COPD increases with pack-years of smoking or, less often, with ongoing occupational exposure to inhaled toxins or irritants[23-25].
Although daily symptoms are present in a minority of people with
asthma symptoms in COPD are more likely to be constant and progressive,
reflecting the fact that airway obstruction in COPD is not due to the
reversible airway constriction and inflammation of asthma but rather to structural
changes and mechanical derangements with abnormal elastic recoil. Both
asthma and COPD are associated with inflammatory changes in the airway mucosa.
Airway obstruction in COPD is associated with cellular damage and mucus
hypersecretion with inflammation becoming more prominent in exacerbations of
severe disease. Emphysema is characterized by loss of lung elastic recoil and
loss of alveolar structure resulting from inflammatory cell-mediated damage to
bronchioles, alveolar ducts, and alveoli[23-28]. References 1. Raz I et al.(2005). Immune modulation modulation for prevention of type 1 diabetes mellitus. Trends in Biotechnology; 23, 128-133 2. Herold, K.C. and Taylor, L. (2003) Treatment of Type 1 Diabetes with anti-CD3 monoclonal antibody: induction of immune regulation? Immunol. Res. 28, 141-150
3. Chatenoud, L. et al. (1994) Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc. Natl. Acad. Sci. U. S. A. 91, 123-127
4. Herold, K.C. et al.(2002) Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus. N. Engl. J. Med. 346, 1692-1698
5. Shanahan F. Host-flora interactions in inflammatory bowel disease. Inflamm Bowel Dis 2004; 10(Suppl 1):S16-S24
6. Lichtenstein GR, Bala M, Han C, et al. Infliximab improves quality of life in patients with Crohn's disease. Inflamm Bowel Dis 2002; 8:237-243
7. Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history, and progression of ulcerative colitis: a long-term follow-up of 1116 patients. Dig Dis Sci 1993; 38:1137-1146
8. Munkholm P, Langholz E, Davidsen M, Binder V. Disease activity courses in a regional cohort of Crohn's disease patients. Scand J Gastroenterol 1995; 30:699-706
9. Munkholm P. Crohn's disease: occurrence, course and prognosis: an epidemiologic cohort-study. Dan Med Bull 1997; 44:287-302
10. Rutgeerts P, Geboes K, Vantrappen G, et al. Predictability of the postoperative course of Crohn's disease. Gastroenterology 1990; 99:956-963
11. Cosnes J, Nion-Larmurier I, Beaugerie L, et al. Impact of the increasing use of immunosuppressants in Crohn's disease on the need for intestinal surgery. Gut 2005; 54:237-241
12. Powrie F, Leach MW, Mauze S, et al. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol 1993; 5:1461-1471
13. Morrissey PJ, Charrier K, Braddy S, et al. CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med 1993; 178:237-24
14. Plevy S, Salzberg B, Van Assche G, et al. A phase I study of visilizumab, a humanized anti-CD3 monoclonal antibody, in severe steroid-refractory ulcerative colitis. Gastroenterology 2007; 133:1414-1422
15. Belghith M, Bluestone JA, Barriot S, et al. TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 2003; 9:1202-1208
16. You S, Leforban B, Garcia C, et al. Adaptive TGF-beta-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc Natl Acad Sci U S A 2007; 104:6335-6340
17. Kamanaka M, Kim ST, Wan YY, et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 2006; 25:941-952
18. Perruche S, Zhang P, Liu Y, et al. CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med 2008; 14:528-535
19. Raghavendran K et al. Pharmacotherapy of acute lung injury and acute respiratory distress syndrome.Curr Med Chem. 2008;15(19):1911-24
20. National Heart Lung and Blood Institute, National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD; 2007. NIH Publication No. 07-4051
21. Global Initiative for Asthma. Pocket Guide for Asthma Management and Prevention. Available at: http://www.ginasthma.org
22. Jenkins MA et al. Factors in childhood as predictors of asthma in adult life. BMJ. 1994;309:90-93
23. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Available at: http://www.goldcopd.com
24. American Lung Association. ALA Asthma Survey: Executive Summary. Available at: http://www.lungusa.org
25. Walter RE et al. Systemic inflammation and COPD: the Framingham Heart Study. Chest. 2008;133:19-25
26. Beeh KM et al. Clinical application of a simple questionnaire for the differentiation of asthma and chronic obstructive pulmonary disease. Respir Med. 2004;98:591-597
27. Decramer M et al. Asthma and COPD: differences and similarities. With special reference to the usefulness of budesonide/formoterol in a single inhaler (Symbicort) in both diseases. Int J Clin Pract. 2005;59:385-398
28. Sutherland ER et al. Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma. J Allergy Clin Immunol. 2003;112:819-827 |