- Findings Suggest Protein May Play an Important Role in the Pathobiology of Severe Asthma, Identify Potential New Biomarker for Severity of Disease
GAITHERSBURG, Md., Nov. 14 /PRNewswire/ -- MedImmune, Inc. today announced the publication of the first clinical results studying chitinase-like protein, YKL-40, suggesting that the molecule may play an important role in determining the mechanisms of severe asthma. Data to be published in the November 15, 2007 issue of The New England Journal of Medicine suggest that circulating serum levels of YKL-40, also known as HcGP-39, are increased in patients with asthma, compared to those without disease, and correlate with asthma severity. Supplementing preclinical evidence demonstrating that chitinases play a critical role in asthma, these data suggest that YKL-40 may serve as a potential new biomarker for disease severity, prompting further clinical study.
"This study represents the collaborative efforts between MedImmune researchers and other leaders in the field of respiratory illness to explore novel biologic pathways to disease," said Anthony Coyle, Ph.D., vice president, respiratory, inflammation and autoimmune disease research. "MedImmune is at the forefront of chitinase research, and these results add YKL-40 to the host of novel approaches we are exploring in clinical trials across multiple inflammatory diseases."
Recent pre-clinical data suggest that chitinases are effector models in asthmatic airway inflammation. As the first clinical experience in patients with asthma, this new study evaluated the serum levels of related chitinase- like protein YKL-40 and the potential correlation to disease severity. Data from this early-phase study suggest that serum YKL-40 levels were significantly elevated in patients with severe asthma and that this molecule may be a biomarker for asthma severity, compared to patients with milder disease or to those without asthma. Additionally, a post-hoc analysis suggested that among patients with severe asthma, YKL-40 levels correlated with clinical measurements associated with severe disease, including the frequency of corticosteroid tapers, doses of oral corticosteroids and the frequency of rescue inhaler use. Investigators concluded that YKL-40 may play an important role in the pathobiology of severe asthma, warranting further study of this molecule as a potential novel pathway to disease.
"We hope that these results may encourage prospective studies to gain greater understanding of how YKL-40 levels are associated with disease activity, and the potential of this protein as a biologic target for asthma management and research," said Geoffrey Chupp, lead investigator, section of pulmonary and critical care medicine and department of internal medicine, Yale University School of Medicine. "While additional data are needed to support these findings, at this stage, we believe the results demonstrate that the biology of YKL-40 should be incorporated into the understanding of asthma pathobiology."
In the study of 253 adult patients, investigators evaluated serum levels of YKL-40 across three asthma and control cohorts. Based on an exploratory analysis of serum samples of an established cohort of subjects from Yale University (n=135), samples were then evaluated from sets of patients at the University of Wisconsin (n=66) and the University of Paris (n=52). Levels of circulating YKL-40 were measured across all cohorts, and findings were correlated with asthma severity, airway expression of the molecule and parameters of airway remodeling. Additionally, the expression of YKL-40 in the airway and its relationship to serum levels of the molecule was evaluated in the Paris cohort alone.
"The number of cells expressing YKL-40 observed in the lung was significantly increased among patients with asthma compared to the control group and correlated positively with serum levels of the molecule," said Marina Pretolani, Ph, D., Inserm Unit 700 and Denis Diderot Faculty of Medicine, University of Paris 7. "Importantly, elevated expression of YKL-40 in serum and lung is associated with the degree airflow obstruction, the main hallmark of asthma severity. Finally, YKL-40 overexpression occurs in patients taking high-dose, long-term inhaled corticosteroids, suggesting that YKL-40 production is refractory to current asthma treatments and, therefore, it may represent an alternative therapeutic target for severe asthma."
Data demonstrate that serum YKL-40 levels were significantly elevated in patients with severe asthma compared to the control group. In the Yale cohort, median levels of YKL-40 in the serum from patients with asthma were 69.7 ng/ml compared to 58.3 ng/ml in those without asthma (P=0.02). Interquartile ranges were 40.0-107.1 and 40.0-73.3, respectively. Findings in the Yale cohort were subsequently confirmed in the Paris cohort. Median levels of YKL-40 in the serum from patients with asthma were 97.7 ng/ml compared to 41.5 ng/ml in those without asthma (P=0.002). Interquartile ranges were 26.8-103.5 and 11.5-57.8, respectively. Additionally, according to bronchial biopsies taken in the Paris cohort, the expression of YKL-40 was 16.2 positive cells per millimeter squared compared to 3.1 positive cells per millimeter squared (P=0.005) with interquartile ranges of 9.1-30.2 and 2.1- 7.4, respectively.
Compared to the control group, the results suggest that among patients with asthma, serum YKL-40 levels may be associated with asthma severity, and inversely with lung function. To determine this potential correlation, investigators evaluated the expression of YKL-40 in tissue cells, thickness of sub-epithelial basement membrane (SBM), levels of circulating YKL-40 in the lungs, and pulmonary function.
According to bronchial biopsies taken in the Paris cohort, lung YKL-40 levels correlated with serum YKL-40 levels (r=0.548, P < 0.001). In this cohort, the median level of tissue cells expressing YKL-40 in the lungs correlated positively with asthma severity in all patients studied (P=0.003). The median number of YKL-40 expressing tissue cells were 13.7 per millimeter squared for those with mild disease (interquartile range 3.0-28.3), 11.3 per millimeter squared for those with moderate disease (7.9-17.5), and 23.1 per millimeter squared for those with severe asthma (15.2-54.1), compared to 3.1 per millimeter squared for those without disease (2.1-7.4). There was a significant correlation between SBM thickness and the serum YKL-40 levels (r=0.51, P=0.003). Median SBM was thicker in patients with mild 9.4 microM (interquartile range 7.0-10.9) and moderate asthma 9.2 microM (8.8-10.80) compared to those without disease 4.7 microM (3.9-4.9, P<0.001) and were highest in patients with severe asthma 12.4 microM (11.5-13.4, P=0.003).
In all three cohorts, levels of circulating YKL-40 correlated to asthma severity. In the Yale cohort, median YKL-40 levels were 49.11 ng/ml (interquartile range 36.7-94.2) in patients with mild asthma, 68.43 ng/ml (38.0-88.0) in those with moderate asthma, and 77.0 ng/ml (44.6-158.4) in patients with severe asthma. (P for trend = 0.003). In the Paris cohort, median levels were 45.5 ng/ml (24.5-78.5) in patients with mild asthma, 41.0 ng/ml (25.0-67.0) in those with moderate asthma, and 94.0 ng/ml (72.0-181.5) in severe asthmatics (P for trend = 0.007). In the Wisconsin cohort, media levels were 49.11 ng/ml (36.7 - 94.2) in patients with mild asthma, 68.43 ng/ml (38.0 - 88.0) in those with moderate asthma, and 77.0 ng/ml (44.6 - 158.4) in severe asthmatics (P for trend < 0.05). Additionally, serum YKL-40 levels correlated inversely with pulmonary function in all three cohorts. YKL- 40 levels correlated inversely with FEV1 (Yale, r= -0.22, P=0.01; Wisconsin, r= -0.33, P=0.009; and Paris, r= -0.21, P=0.005).
Chitinase in Inflammatory Disease
Chitinase is a protein that is believed to be expressed at high levels in patients with inflammatory diseases such as asthma and rheumatoid arthritis. In preclinical studies, chitinase was found at high levels in patients with asthma, while the molecule was undetectable in those without the disease. Preclinical study data indicate that blocking chitinase in animals eased lung inflammation, suggesting that chitinase may potentially play a role in the treatment of asthma and other inflammatory diseases.
Asthma is a chronic disease of the airways that may cause wheezing, breathlessness, chest tightness and coughing. According to the U.S. Centers for Disease Control and Prevention (CDC), more than 30 million Americans reported having a history of asthma in 2003, including nine million children. About 20 million said they currently had asthma. In 2000, the CDC reported that there were more than 10 million asthma-related outpatient visits to private physician offices and hospital clinics. The National Institutes of Health (NIH) have estimated asthma-related healthcare costs in the U.S. at $14 billion annually.
MedImmune strives to provide better medicines to patients, new medical options for physicians and rewarding careers to employees. With approximately 3,000 employees worldwide and headquarters in Maryland, MedImmune is dedicated to advancing science and medicine to help people live better lives and is wholly owned by AstraZeneca plc (LSE: AZN.L, NYSE: AZN). For more information, visit MedImmune's website at http://www.medimmune.com.
|SOURCE MedImmune, Inc.|
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