Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
  • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2500/00—Screening for compounds of potential therapeutic value
  • G01N2500/10—Screening for compounds of potential therapeutic value involving cells
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/10—Musculoskeletal or connective tissue disorders
  • G01N2800/101—Diffuse connective tissue disease, e.g. Sjögren, Wegener's granulomatosis
  • G01N2800/102—Arthritis; Rheumatoid arthritis, i.e. inflammation of peripheral joints
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/10—Musculoskeletal or connective tissue disorders
  • G01N2800/105—Osteoarthritis, e.g. cartilage alteration, hypertrophy of bone
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N2800/00—Detection or diagnosis of diseases
  • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

• the present invention relates to ratios of collagen peptide epitopes recognized by antibodies, their use in treatment, diagnosis, detection and monitoring of disease activity and progression and conditions relating to collagen, assay kits to determine the ratios, screening methods employing the ratios to determine the ability of agents to affect the ratios, and agents identified by such screening methods.
• Osteoarthritis a debihtative and painful condition, represents a complex of interactive degradative and reparative degenerative processes in cartilage and bone with secondary inflammatory changes. It results in a progressive degeneration of diarthrodial joints in particular a loss of articular cartilage, resulting in a loss of joint function.
• OA Osteoarthritis
• Recent studies have demonstrated that excessive degradation, involving cleavage and denaturation of most particularly (but not exclusively) type II collagen in human articular cartilage is implicated in osteoarthritis (Hollander, A.P. et al, J. Clin. Invest. 93:1722- 1732 (1994); Dodge, G.R. and Poole, A.R., J. Clin. Invest.
• OA Primary or idiopathic OA affects interphalangeal joints, and other small joints as well as large joints, such as the hip or knee, involvement of the proximal interphalangeal joints of the hands leads to the formation of Bouchard's nodes in contrast, involvement of the distal interphalangeal joints involves Heberden's nodes.
• the disease may involve one particular joint, or it may be more generalized and involve multiple joints.
• OA may be genetically transmitted (such as a consequence, for example, of a mutation in the type II collagen COL2A1 gene) and therefore is known as familial OA.
• OA may develop in patients after traumatic injury or damage to chondrocytes associated with abnormal deposits of the cartilage matrix found in metabolic diseases such as hemochromatosis, ochronosis or alkaptonuria, Wilson's disease, and Gaucher's disease.
• Idiopathic OA may result from disturbances in cartilage metabolism caused by endocrine disorders (Poole A.R., and Howell D.S., Etiopathogenesis of Osteoarthritis. In: Diagnosis and Medical/Surgical Management (3 rd ed.), Moskowitz, R.W. et al. (Eds), pp. 29-37, Philadelphia , Saunders Company (2001)..
• Mineralization of cartilage matrix is a feature of OA and is associated with chondrocyte hypertrophy. See Poole, A.R. and Howell, D.S. (200X) supra.
• Rheumatoid arthritis is another example of a disease of the musculoskeletal system in which joint cartilages are destroyed as part of an inflammatory condition involving inflamed synovium lining the joint cavity.
• This inflammation involves the erosive destruction of articular cartilage and its type II collagen by collagenases as well as destruction of bone containing type I collagen (see Henderson, B. et al. supra).
• Rheumatoid arthritis usually involves multiple joints.
• Assays of collagen epitopes have been used to detect the resorption of bone such as in osteoporosis (type I collagen cross-links) (see Delmas, P. and Garnero, P. Biological markers of bone turnover in osteoporosis. In J.C. Stevenson, RE. Lindsay, (eds), Osteoporosis, pp. 117-136, London, Chapman and Hall, 1998) and the turnover/resorption of hyaline cartilage in arthritis (type II collagen degradation products) (see Garnero P. et al, Arthritis Rheumatis 43:953-961, 2000 [Robin Poole to check]).
• joint space narrowing is ordinarily used to determine loss of articular cartilage in osteoarthritis or rheumatoid arthritis or in any other types of arthritis. This may require hundreds of patients and a two-three year period of study to accurately measure in population studies, such as in clinical trials for drug efficacy, loss at joint space with disease progression in osteoarthritis. Due to the more rapid erosive character of rheumatoid arthritis (RA), a period of 1-1 1/2 years may be sufficient to determine joint space loss in RA.
• RA rheumatoid arthritis
• a method of monitoring a collagen-related disease comprising determining a ratio of Cl, 2C neoepitope to C2C neoepitope in a subject.
• a higher result is predictive of greater progression of osteoarthritis and a lower result is predictive of greater progression of rheumatoid arthritis.
• an increase in the ratio indicates or relates to progression of osteoarthritis and a decrease in the ratio indicates a progression of rheumatoid arthritis.
• the subject does not exhibit generalized osteoarthritis or exhibits rheumatoid or other inflammatory erosive arthritis.
• the invention provides a method of monitoring arthritis involving joint destruction other than osteoarthritis, comprising determining a level of Cl, 2C neoepitope to C2C neoepitope in a subject, wherein a change in the level indicates a change in rate of progression of joint destruction of the arthritis.
• a decrease in the level of Cl, 2C neoepitope to C2C neoepitope in a subject is indicative of rheumatoid arthritis.
• a further embodiment of the invention includes a method of monitoring efficacy of a therapeutic regimen for treating a collagen-related disease (preferably osteoarthritis or rheumatoid arthritis), comprising determining a ratio of C1,2C epitope to C 2C epitope in a subject, a change in the ratio indicating a change in severity of the disease.
• a collagen-related disease preferably osteoarthritis or rheumatoid arthritis
• Another embodiment is a method of identifying an agent for treating a collagen- related disease (preferably osteoarthritis or rheumatoid arthritis), comprising administering to a subject an agent to be tested, and determining a ratio of C1,2C epitope to C 2C epitope in the subject, a change in the ratio indicating a change in severity of the disease
• a collagen- related disease preferably osteoarthritis or rheumatoid arthritis
• a further embodiment is a pharmaceutical composition for a collagen-related disease (preferably osteoarthritis or rheumatoid arthritis) comprising an agent identified by the above method in an amount effective to change the ratio or reduce the change in the ratio relative to an untreated subject.
• a collagen-related disease preferably osteoarthritis or rheumatoid arthritis
• kits for determining a ratio of C 1 ,2C neoepitope to C 2C epitope in a biological sample comprising:
• Still another embodiment is an improvement in a method of treating a collagen- related disease (preferably osteoarthritis or rheumatoid arthritis), the improvement comprising determining a ratio of C1,2C neoepitope to C 2C neoepitope in a subject being treated, wherein a change in the ratio correlates to a change in progression of the disease.
• a collagen- related disease preferably osteoarthritis or rheumatoid arthritis
• Samples may be removed with a syringe from peripheral blood and allowed to clot to produce serum for analysis or prevented from clotting, to permit analysis of plasma, by an anti-coagulant such as heparin or ethylenediamine tetraacetic acid.
• an anti-coagulant such as heparin or ethylenediamine tetraacetic acid.
• the present invention relates to the determination of ratios of collagen epitopes in the detection of the relative cleavage and synthesis of type II collagen in patients with osteoarthritis, rheumatoid arthritis, and other types of arthritis involving joint destruction.
• C2C refers to "Collagen type "2" "Cleavage and is used in an assay specific for type II collagen.
• Cl, 2C refers to "Collagen type “1” & “2" "Cleavage and is used in an assay specific for both type I & II collagen.
• Col II stands for type II collagen.
• the term "3/4" refers to the cleavage of type II collagen into two pieces, namely, (1) the length of the collagen, and (2) 3 A the length of the collagen.
• C refers to the "C-terminus” at the end of the % collagen piece.
• short and long refer to the neoepitope that is detected. Both assay kits described above detect the neoepitope that is revealed after collagen is cleaved. The “short” detects a shorter portion of the "Long" sequence of amino acids.
• An antibody as described herein, refers to an immunoglobulin molecule or a binding fragment thereof (either enzymatically or recombinantly produced).
• An antibody fragment is a portion of an antibody such as F(ab') , F(ab) 2 , Fab', Fab, Fv, sFv and the like. Regardless of structure, an antibody fragment binds with the same antigen that is recognized by the intact antibody.
• antibody fragment also includes any synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex.
• antibody fragments include isolated fragments consisting of the variable regions, such as the "Fv” fragments consisting of the variable regions of the heavy and light chains, recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker ("scFv proteins”), and minimal recognition units consisting of the amino acid residues that mimic the hypervariable region.
• variable regions such as the "Fv” fragments consisting of the variable regions of the heavy and light chains
• scFv proteins recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker
• minimal recognition units consisting of the amino acid residues that mimic the hypervariable region.
• Neoepitopes are epitopes that are not expressed in the native protein (collagen) and are only exposed in protein that has been modified by a change in structure. Such a change in structure to reveal a neoepitope may follow proteolytic cleavage (collagenase), a conformational change following activation or following binding of the protein to another protein.
• Osteophytes (Heberden's and Bouchard's nodes) refer to extra bone the body produces and deposits in an osteoarthritic joint that can impede its movement. These bony growths are also known as bone spurs. The osteophytes may be found in arthritic affected areas such as joint or disc spaces where the cartilage has deteriorated.
• Osteoarthritis refers to a degenerative joint disease occurring chiefly in older persons, characterized by degeneration of the articular cartilage, hypertrophy of bone at the margins, and often limited inflammatory changes in synovial membrane. It is accompanied by pain and stiffness, particularly after prolonged activity. It is a form of arthritis where osteophytes are present in one or more joints.
• Generalized osteoarthritis refers to a variant form of osteoarthritis that develops spontaneously and affects numerous joints with no readily identifiable cause. Its mains symptoms are pain and degeneration of joint cartilage, however, it shows a marked predilection for the fingers, knees, hips, feet and spine with considerable remodeling of bone tissue. It is a form of arthritis where osteophytes are present in one or more joints and there is also hand osteoarthritis as indicated by > 2 Heberden's nodes in at least 1 hand. Heberden's nodes refers to small hard nodules, formed usually at the distal interphalangeal articulations of the fingers produced by calcific spurs of the articular cartilage and associated with interphalangeal osteoarthritis.
• RA Rheumatoid arthritis
• RA Rheumatoid arthritis
• the disease is often progressive and results in pain, stiffness, and swelling of joints. In late stages deformity and ankylosis develop. The cause of RA is unknown.
• Factors associated with RA include the possibility of infectious triggers, genetic predisposition, and autoimmune response.
• the primary targets of inflammation are synovial membranes and articular structures. Other organs are affected as well. Inflammation, proliferation, and degeneration typify synovial membrane involvement. Joint deformities and disability result from the erosion and destruction of synovial membranes and articular surfaces.
• a biological sample can be from human, dog, bovine, horse, guinea pig, sheep, pig, rabbit, mouse or rat.
• it can be selected from the group consisting of synovial fluid, serum, plasma, urine, broncheoalveolar lavage, medium extracts and cartilage extracts.
• OA knee osteoarthritis
• ELISA C2C and C1,2C assays and knee x-rays were performed at baseline and 18 months. Progression was defined as a baseline-to- 18 -month increase in joint space narrowing grade. Progression was also examined as a K/L grade increase. Knees with the highest grade at baseline were excluded. Odds ratios for progression were estimated from logistic regression using generalized estimating equations to validly use data from both knees.
• mean colratio was 4.40 (S,D. 11.00, range 0.17-94.03).
• mean colratio in the progressors was 4.60 and in the non-progressors 4.08.
• mean colratio was 6.71 and 3.64 in the progressors and non-progressors, respectively.
• Baseline colratio predicted baseline to 18 month progression in the group without generalized OA but not in the group with generalized OA.
• Each 20-unit increment in colratio was associated with a significant 1.46-fold increase in the odds of joint space progression, and a 1.78-fold increase in the odds of K/L progression. C1,C2 and C2C separately were not predictive of progression.
• baseline serum colratio predicted knee OA progression over the following 18 months, only in the subset without evidence of generalized OA.
• the ratio may be more predictive of progression than individual assay values since it may reflect increased secondary cleavage of type II collagen (with selective cleavage of the larger C2C epitope giving rise to the C1,2C epitope) based upon results from other studies.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Immunology (AREA)
• Biomedical Technology (AREA)
• Hematology (AREA)
• Urology & Nephrology (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Rheumatology (AREA)
• Molecular Biology (AREA)
• Medicinal Chemistry (AREA)
• Pathology (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Microbiology (AREA)
• Biotechnology (AREA)
• General Physics & Mathematics (AREA)
• Biochemistry (AREA)
• Analytical Chemistry (AREA)
• Physics & Mathematics (AREA)
• Food Science & Technology (AREA)
• Cell Biology (AREA)
• Gastroenterology & Hepatology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Organic Chemistry (AREA)
• Rehabilitation Therapy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Diabetes (AREA)
• Endocrinology (AREA)
• Toxicology (AREA)
• General Chemical & Material Sciences (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Pain & Pain Management (AREA)
• Physical Education & Sports Medicine (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Peptides Or Proteins (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (2)

Family

ID=32069723

Family Applications (1)

Country Status (7)

Cited By (1)

Families Citing this family (5)

Family Cites Families (2)

• 2003
  • 2003-09-30 US US10/673,647 patent/US20040132064A1/en not_active Abandoned
  • 2003-09-30 AU AU2003279076A patent/AU2003279076A1/en not_active Abandoned
  • 2003-09-30 KR KR1020057005375A patent/KR20050084608A/ko not_active Withdrawn
  • 2003-09-30 CA CA002500670A patent/CA2500670A1/en not_active Abandoned
  • 2003-09-30 JP JP2004541914A patent/JP2006501479A/ja active Pending
  • 2003-09-30 WO PCT/US2003/030853 patent/WO2004031725A2/en not_active Ceased
  • 2003-09-30 EP EP03770587A patent/EP1549354A4/en not_active Withdrawn

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events