Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-08-11
2001-08-21
Budens, Robert D. (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007920, C436S543000, C436S546000
Reexamination Certificate
active
06277586
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the use of recombinant DNA technology for the transformation of a host organism with glutamic acid decarboxylase
65
(GAD
65
) for the expression of GAD
65
polypeptides. Also encompassed are methods of using GAD
65
polypeptides diagnostically and therapeutically in autoimmune disease.
2. Description of the Background Art
Insulin-ependent diabetes mellitus (IDDM; type I diabetes) is one of the most common metabolic disorders. In the United States, IDDM affects approximately one in 300 to 400 people, and epidemiological studies suggest that its Incidence is increasing. The disease results from the autoimmune destruction of the insulin-producing &bgr;-cells of the pancreas. More specifically, the preonset stage is characterized by “insulitis”, in which lymphocytes infiltrate the pancreatic islets and selectively destroy the &bgr;-cells. The typical IDDM presentation of hyperglycemia appears only after at least 80% of the insulin-producing &bgr;-cells are lost. The remaining &bgr;-cells are destroyed during the next few years.
Although insulin therapy allows most IDDM patients to lead normal lives, this replacement is imperfect and does not completely restore metabolic homeostasis. Thus, severe complications which result in dysfunctions of the eye, kidney, heart, and other organs are common in IDDM patients undergoing insulin therapy. Because of this, it is highly desirable to extend the latency period (e.g., through administration of immunosuppressant drugs) between the start of &bgr;-cell destruction and the actual requirement of insulin replacement (i.e., when 80% of the &bgr;-cells are destroyed). Therefore, a diagnostic test which determines the beginning of &bgr;-cell destruction would allow the clinician to administer immunosuppressant drugs (Silverstein, et al.,
New England Journal of Medicine
, 319:599-604,1988) to extend this latency period and thus significantly delay the onset of insulin replacement side effects.
Many IDDM patients have sera which contain antibodies to a 64 kD molecule (Baekkeskov, et al.,
J. Clin. Ivest
., 79:926-934, 1987; Atkinson, et al.,
Lancet
, 335:1357-1360, 1990), to islet cell cytoplasmic (ICA) molecules or islet cell surface (ICSA) molecules (Bottazzo, et al, Lancet, 1:668-672, 1980), or to insulin (Palmer, et al.,
Science
, 222:1137-1139, 1983; Atkinson, et al.,
Diabetes
, 35:894-898, 1986). Atkinson and coworkers (Atkinson, et al.,
Lancet
, 335:1357-1360, 1990) have demonstrated that the presence of antibodies to the 64 kD molecule in human sera appears to be the earliest and most reliable indicator that onset of IDDM symptoms will eventually occur.
Recently, Baekkeskov and coworkers established that the 64 kD molecule and glutamic acid decarboxylase (GAD) have several antigenic epitopes in common and thus they may be identical or very similar molecules. Although this identification is an important finding, the use of this information as a diagnostic tool for predicting IDDM is quite cumbersome and limited unless knowledge of the molecular biology of GAD is known. Consequently, the cloning and subsequent production of large quantities of the 64 kD molecule, or a GAD molecule which is antigenically substantially identical to the 64 kD molecule, will allow the development of a diagnostic kit designed to predict IDDM. The present invention provides a means for accomplishing this result.
SUMMARY OF THE INVENTION
The present invention arose out of the discovery that recombinant DNA technology could be used to produce eukaryotic GAD
65
polypeptide and that GAD
65
polypeptide could be used in the diagnosis and therapy of patients with autoimmune disease. Particularly relevant is the use of cloned eukaryotic GAD
65
polypeptide in the diagnosis of patients having, or at risk of having, insulin-dependent diabetes mellitus (IDDM).
A major advantage of the present invention is that it provides the art with a ready source of eukaryotic GAD
65
polypeptide corresponding to that purified from natural sources, while avoiding the problems associated with the isolation of naturally occurring eukaryotic GAD
65
polypeptide when separating it from other eukaryotic non-GAD
65
polypeptides. This absence of other eukaryotic non-GAD
65
polypeptides is significant in that it allows the development of test systems which will only detect antibodies specifically reactive with GAD
65
polypeptides.
Another advantage of providing eukaryotic GAD
65
polypeptide in host cells is that by so doing, it is possible to obtain much larger quantities of the polypeptide than are currently practicably available from natural sources. As a consequence, not only is it possible to use the polypeptide of the invention to more accurately classify patients with such autoimmune diseases as IDDM, but it is also now possible to provide commercially useful quantities of GAD
65
polypeptide for use in diagnostic systems.
REFERENCES:
patent: 5475086 (1995-12-01), Tobin et al.
patent: 5512447 (1996-04-01), Baekkeskov et al.
patent: 5645998 (1997-07-01), Atkinson et al.
patent: 5674978 (1997-10-01), Tobin et al.
patent: 5705626 (1998-01-01), Tobin et al.
patent: 5762937 (1998-06-01), Atkinson et al.
patent: 5792620 (1998-08-01), Lernmark et al.
patent: 5846740 (1998-12-01), Tobin et al.
patent: 5998366 (1999-12-01), Tobin et al.
patent: 6011139 (2000-01-01), Tobin et al.
Erlander Mark G.
Kaufman Daniel L.
Tobin Allan J.
Budens Robert D.
Burns Doane , Swecker, Mathis LLP
Regents of the University of California
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