Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-10-06
2001-09-04
Smith, Lynette R. F. (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C436S501000, C436S504000, C436S536000, C436S540000, C436S542000, C436S804000, C436S811000
Reexamination Certificate
active
06284473
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of neurology and multiple sclerosis. More specifically, the present invention relates to an assay for measuring urinary myelin basic protein-like material, more particularly the urinary p-cresol sulfate component, and the use of this assay as a correlate of multiple sclerosis status.
2. Description of the Related Art
Multiple sclerosis (MS), an inflammatory, primary demyelinating disease of the central nervous system (CNS) affecting an estimated 350,000 persons in the United States (1), is typified by a chronic and unpredictable course. This variable course and the associated heterogeneity of the disease renders clinical trials involving large groups and clinical management of the individual patient problematic. Based on disease course, multiple sclerosis patients are usually categorized (2,3) as relapsing-remitting (RR), relapsing progressive (RP), primary progressive (PP) and secondary progressive (SP), according to the clinical appearance and persistence of neurological deficit. The development of disease progression, whether from onset, as in PP-MS, or as SP-MS subsequent to an earlier period of relapses, can be viewed as the failure of remission. The failure of remission (i.e., progression of the disease) is the principal cause of disability and decline in the quality of life.
The natural history of MS has been studied extensively for clinical features or laboratory measurements which might predict, anticipate or parallel the future course of disease. Clinical characteristics which appear to predict a future progressive course include: (a) male gender; (b) later age of onset of the disease; (c) corticospinal and cerebellar involvement; (d) increased number of relapses in the first five years; and (e) shorter interval between the first and second relapse (2-4). The clinical scales for assessing progression of disability have certain limitations (5), but, in general, the functional status in a population of MS patients is better than usually envisioned (6), and patients, even with chronic progressive disease, may go through periods of spontaneous stability (7). This imprecision in clinical patterns and natural history requires clinical markers for signaling progression (8).
Several laboratory methods, including HLA typing (9) and cerebrospinal fluid (CSF) levels of tumor necrosis factor-a (10) have been reported to predict or parallel subsequent disease course in multiple sclerosis. Confirmation of these reported relationships have either not been successful (11) or conflicting (2). Serial cranial MRI, with or without gadolinium, represents another measure of clinical disease activity in MS (5, 12). Cranial MRI may predict the development of MS after initial signs (13) serve as a presumed surrogate marker in early MS (14) and cranial MRI demonstrates increasing lesion burden with longer duration of disease (12). The cranial MRI findings which are indicative of a chronic progressive course or which mark the transition from relapsing-remitting to chronic progressive disease are uncertain (15). Newer MRI techniques, such as magnetization transfer (16), may more accurately demonstrate the physiological changes of chronic progressive-multiple sclerosis. Whatever the technique, cranial MRI furnishes an incomplete record about the change to a chronic progressive course since such change often involves the spinal cord.
Given the encephalitogenic properties of myelin basic protein (MBP) for inducing experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis (MS), MBP has been extensively characterized immunologically. Human MBP is encoded by a single gene comprising seven exons on human chromosome 18, where it resides on the 3′ side of the larger golli-mbp gene (41). Due to alternate splicing of the seven exons, MBP may appear in at least five isoforms, with an 18.5 Kd molecule comprising 170 amino acid residues predominating in central nervous system (CNS) myelin of adults (42). Extensive post-translational modification of MBP results in many charge isomers, such that MBP is comprised of a family of molecules (43). MBP has many epitopes for T and B cells, which, for B cells, conform to a flexible model (44). Some of the B cell epitopes, notably those in the carboxyl residues of MBP peptide 80-89, are cryptic and not expressed in the intact molecule of MBP (45).
Myelin basic protein (MBP) comprises 30% of CNS myelin proteins (17). Material, designated as myelin basic protein-like material (MBPLM), i.e., reactive with antibodies to myelin basic protein, normally exists at very low levels in CSF but increases after acute CNS myelin damage (18, 19). Serial sampling of CSF is not feasible, but the level of CSF myelin basic protein-like material in a multiple sclerosis patient with recent clinical worsening is predictive of a response to a regimen of intravenous methylprednisolone and oral prednisone (20). CSF myelin basic protein-like material has a molecular weight of >30,000 and appears to be bound to a carrier molecule (21). Myelin basic protein-like material in CSF is best recognized by an antibody reactive with an epitope that is conformationally present in the intact myelin basic protein molecule and represented by residues 80-89.
Urinary myelin basic protein-like material, usually found in low levels in normal individuals, is present in elevated levels in certain multiple sclerosis patients and is quite different in size and immunochemical features from the myelin basic protein-like material present in CSF (22). Urinary MBPLM has a molecular weight of <1000, is not bound to any other substances and appears to be similar to myelin basic protein residues 83-89 (22, 23). The level of urinary myelin basic protein-like material, unlike the level of myelin basic protein-like material in CSF, does not reflect acute disease activity in multiple sclerosis and correlates best with the existence of chronic progressive disease (23).
Recombinant interferon beta-1b (IFN&bgr;-1b) is the first therapeutic agent which can alter the natural history of relapsing-remitting multiple sclerosis by reducing the number and severity of relapses and the volume of white matter detected by cranial MRI (24). Although disease progression was not an end point in that trial of IFN&bgr;-1b, there was a non-significant trend toward an effect of treatment on disease progression (24). Although not FDA-approved, IFN&bgr;-1b has been shown in a European study to reduce progression in SP-MS (Kappos et al Lancet November, 1998).
Thus, the prior art is deficient in the lack of effective means of determining the failure of remission and/or diagnosing the presence of a progressive phase in patients having multiple sclerosis.
The present invention fulfills this longstanding need and desire in the art.
SUMMARY OF THE INVENTION
In the multi-center, randomized placebo-controlled trial of alternate-day injections of recombinant interferon beta-1b (IFN&bgr;-1b) in relapsing-remitting (RR) multiple sclerosis, urine specimens were collected periodically from all patients (n=64) in two of the clinical test sites over the two years of the study. Urine was also collected over two consecutive 24 hour periods from 43 patients from a third center. Urine samples were assayed for their content of myelin basic protein-like material, the level of which was correlated with a variety of clinical changes, cranial MRI results and the development of progressive disease. The level of urinary myelin basic protein-like material correlated with a secondary progressive (SP) course and with the number and total area of lesions on T2-weighted cranial MRI. A rise in the level of urinary myelin basic protein-like material antedates the clinical transition from a relapsing-remitting to a chronic progressive course. The randomized entry of patients led to significant differences in urinary myelin basic protein-like material among the three treatment groups, thus precluding correlation studies of treatment effects.
Bradley, Jr. Edwin Luther
Burgard Sheila Loughran
Cao Ligong
Coward Lori
Jackson Patricia L.
Adler Benjamin Aaron
Baskar Padma
Smith Lynette R. F.
UAB Research Foundation
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