Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1997-03-04
1999-08-10
Feisee, Lila
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 792, 435 793, 435 794, 435326, 5303871, 5303879, 5303881, G01N 3353, C12N 512, C07K 1600
Patent
active
059357967
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to methods and compositions for early diagnosis, monitoring and treatment of cartilage degenerative conditions, including forms of arthritis. In particular, the invention relates to a peptide generated as a result of enzymic breakdown of a major component of cartilage, and a monoclonal antibody which recognises this peptide.
BACKGROUND OF THE INVENTION
Proteoglycans are widely distributed in the body, and consist of a protein core, to which glycosaminoglycan side chains are covalently linked. The major proteoglycan in cartilage is aggrecan. Collagen and aggrecan are the primary components of the articular cartilage which covers the bones of joints, as well as of other cartilages. Other proteoglycans are also found in skin, tendons, cornea, sclera, intervertebral disc, and elsewhere in the body. They vary in the type and number of the glycosaminoglycan side chains, and in the molecular weight of the protein core. Aggrecan comprises chondroitin sulphate and keratan sulphate side chains.
The proteoglycans, including aggrecan, may be affected in a variety of acute and chronic conditions, including connective tissue diseases such as scleroderma and systemic lupus erythematosus and in degenerative joint conditions, or following trauma. Degenerative joint diseases are frequently referred to as arthritis conditions, and include osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and gout, among others.
Arthritis is a crippling musculoskeletal disease that incapacitates millions of people from all walks of life. The two most common forms of arthritis are osteoarthritis (OA) and rheumatoid arthritis (RA). Osteoarthritis alone is the reason for nearly a quarter of all general practitioner consultations. It is present in more than 50% of people over thirty years of age, and statistics released by the Arthritis Foundation of Australia show that one in five Australians is affected. Moreover, the number of people suffering with arthritis is increasing as a consequence of an increasingly elderly population. It is clear that as the incidence of the major killers such as heart disease, cancer and infectious diseases diminishes due to improved public health care, the impact of chronic diseases such as arthritis falls more heavily on the population and on health care systems.
The major feature of both OA and RA is cartilage degradation and loss of aggrecan, the molecule which gives cartilage its unique weight-bearing properties. Most pathological conditions involving proteoglycan destruction are not detected until the disease is relatively advanced. In particular, the initial presenting features of the major arthritides, osteoarthritis and rheumatoid arthritis, are pain, swelling and stiffness. Symptoms do not manifest themselves until the degree of cartilage destruction is already significant.
Very little is known of the precise mechanisms underlying the changes in cartilage that lead to damage, or about what causes the loss of aggrecan and the eventual eburnation of the articular surface. Clearly there is an urgent need for: cartilage destruction, and early stages of joint disease before the damage has become so extensive that tissue repair is no longer possible.
In order to identify the early stages, it is necessary to find a marker of the disease that is regularly observed in cases that are clinically well-defined. There is a particularly urgent need for a reliable method of very early detection of cartilage damage. Such methods are, of course, also applicable to monitoring of disease progression, monitoring of the efficacy of methods of therapy, and screening new therapeutic agents.
Methods of detecting proteoglycan products in biological samples have been proposed for this purpose. Thus, for example, U.S. Pat. No. 4,778,768 by Heinegard and Lindblad and U.S. Pat. No. 5,185,245 by Heimer disclose methods of detecting aggrecan or fragments thereof in synovial fluid, and their use in monitoring changes in articular cartilage and monitoring the
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Nakamura et al, in Handbook of Exp. Immunol, 4th Ed, Weir et al. (eds) Blackwell Scienctific Publications, Chapter 27, pp. 27.3-27.4, 1986.
Doege, et al.; "Complete Coding Sequence and Deduced Primary Structure of the Human Cartilage Large Aggregating Proteoglycan, Aggrecan", pp. 894-902; The Journal of Biological Chemistry, vol. 226, No. 2, (Jan. 15, 1991).
Vilamitjana-Amedee, et al.; "Osteoarthristis-Related Changes in Human Articular Cartilage", pp. 219-227; Arthristis and Rheumatism, vol. 33, No. 2 (Feb. 1990).
Fischer, et al.; "Development of Enzyme Immunoassays Specific for Keratan Sulphate- and Cor-Protein-Epitopes of the Large Aggregating Proteoglycan . . . " pp. 285-291; Eur. J. Clin. Chem. Clin Biochem., vol. 32, No. 4, 1994.
Kahnert, et al.; "Determination of Chondroitin-6-Sulphate by a Competitive Enzyme Immunoassay Using a Biotinylated Antigen", pp. 293-299; Eur. J. Clin. Chem. Clin. Biochem., vol. 32/No. 4 (1994).
Feisee Lila
The University of Melbourne
Ungar Susan
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