Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-12-19
2001-08-14
Celsa, Bennett (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S004300, C530S303000, C424S184100
Reexamination Certificate
active
06274549
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of an insulin-like polypeptide without hypoglycaemic effect for delaying or preventing the onset of diabetes or for ameliorating an early stage thereof.
BACKGROUND OF THE INVENTION
Autoimmune diseases are characterized by an abnormal immune response (involving either immune system cells or antibodies) directed against normal autologous (self) tissues. Autoimmune diseases afflict huge numbers of individuals throughout the world.
A normal immune system has the capacity to identify and destroy a large variety of foreign invader organisms such as bacteria and viruses. Remarkably, a normal immune system can readily distinguish foreign substances from self, and thereby is able to react vigorously against potentially pathogenic entities from the environment without harming the host's own cells.
The immune system's non-reactivity to self is termed immunological tolerance. In pathological situations, immunological tolerance to a wide variety of self substances is broken, resulting in an autoimmune response. If of an appropriate nature and of sufficient severity and duration, the anti-self response will result in an autoimmune disease. Cellular immune mechanisms are believed to be primarily involved in insulin dependent diabetes (IDD).
Whereas susceptibility to autoimmune diseases may be inherited through the defective actions of multiple genes, indirect evidence suggests that an interaction with a foreign substance from the environment may also be necessary to induce the pathogenic process that results in disease. One explanation for this is that immunization with the foreign inductive chemical induces a cross-reactive response to self through molecular mimicry or chemical similarity. However, once the autoimmune process has been initiated, other secondary immunizing events involving other self antigens typically occur through the release of intracellular constituents in forms not normally encountered by the immune system. Targeted organs thus become damaged through the combination of all of these events, which leads to the appearance of a clinically recognized disorder only when the disease process has progressed to ablate large numbers of tissue cells so targeted.
A number of strategies have been used or proposed to suppress autoimmune diseases, most notably drugs, such as cyclophosphamide, cyclosporin A, methotrexate, and azathioprine. Steroid compounds, such as prednisone and methylprednisolone, are also employed in many instances. These drugs have limited long term efficacy against both cell- and antibody-mediated autoimmune diseases. Use of drugs is limited by virtue of their toxic side effects which include universal immunosuppression. Prolonged treatment with these drugs inhibits the normal protective immune response to pathogenic microorganisms, thereby increasing the risk of infections. A further drawback is that immune-mediated elimination of aberrant cells is impaired and there is, thus, an increased risk that malignancies will develop in patients receiving prolonged global immunosuppression.
Because the subject invention concerns insulin dependent (Type I) diabetes, a detailed background of diabetes is provided below.
Insulin dependent diabetes
Diabetes mellitus comprises a group of diseases that result in elevation of the blood glucose level because of relative or absolute deficiency in the pancreatic hormone insulin. Insulin is secreted into the blood when food is ingested and primarily directs absorbed nutrients into body stores. Diabetes is a major public health problem affecting at least 5 million and as many as 10 million Americans. The prevalence of the most severe form of IDD is 1 in 300 in the United States.
Chronic elevation of the blood glucose level is the most obvious metabolic effect in diabetes and is associated with progressive damage to blood vessels. This may lead to heart attack, stroke, blindness, peripheral nerve dysfunction, and kidney failure. The frequency and severity of diabetes-related complications are greatest in the insulin dependent form of the disease, in which an immunological destruction of the insulin secreting pancreatic beta cells occurs. The high rate of irreversible complications in IDD occurs despite the availability of insulin replacement through injections given 1-4 times daily.
Insulin and other pancreatic hormones are well known and characterized. See, for example, Steiner et al. (1989) “Chemistry and Biosynthesis of Pancreatic Protein Hormones,” in Endocrinology; DeGroot et al., EDs., W.B. Saunders Company, p. 1263-1289. As described in Steiner et al., the amino acid sequence of insulin is highly conserved across a number of species, including human, monkey, swine, and ox. IDD has proved itself to be predictable both in unaffected relatives of patients with IDD, as well as in persons from the general population. A predisposition to develop clinical diabetes can be detected through several different tests. For example, genetic susceptibility to diabetes has become increasingly definable through the use of molecular biological means, usually from DNA samples obtained from peripheral blood. One major gene involved in the inherited susceptibility to IDD is that located at the HLA-DQ locus. It is currently possible to identify risks varying from essentially none to those as high as 70 fold above those without the genotype. In families a genetic risk as high as 1 in 4 can be estimated for unaffected siblings just through identification of HLA haplotypes shared with the affected proband.
Persons who have just developed IDD or are in process of developing IDD have a number of disease-specific autoantibodies in their blood. Such autoantibodies include those to islet cell antigens (ICA), to beta cell specific proteins of 64 kDa, which are now believed to be the lower molecular isoform of glutamic acid decarboxylase (GAD
65
), to native insulin and proinsulin, and to a number of more minor determinants such as carboxypeptidase-H and heat shock proteins belonging to the hsp-60 family.
Insulin autoantibodies (IAA) are observed in untreated, newly diagnosed IDD patients (Palmer et al. (1983) Science 222, 1337-1339) as well as in apparently unaffected relatives of diabetic probands. Whereas autoimmunity to insulin could directly cause beta-cell damage, could interfere with the action of endogenous insulin, or could have both effects, some investigators suggested that IAA reflect the rate of islet cell destruction and thus act merely as reporters of aggressive islet directed autoimmunity (Ziegler et al. (1989) Diabetes 38, 1320-1325; Vardi (1988) Diabetes Care 11, 736-739).
The spontaneously diabetic non-obese diabetic (NOD) mouse and the BB rat are useful animal models for human IDD. Analysis of these animals provides important insights into the sequence of pathogenic events, and leads to an understanding of the nature of the autoimmunological process. Previous studies from several laboratories have demonstrated that an extended prophylactic course of daily, subcutaneous injections of high doses of insulin protected NOD mice and BB rat from both hyperglycaemia and islet infiltration by mononuclear leucocytes (insulitis) (Atkinson et al. (1990) Diabetes 39, 933-937, Gotfredsen et al. (1985) Diabetologia 28, 933-935).
In addition, prophylactic treatment with high doses of insulin has been reported to prevent diabetes in NOD mice and in BB rats adoptively transferred with spleen lymphocytes from acutely diabetic animals to their non-diabetic counterparts (Thivolet et al. (1991) Diabetologia 34, 314-319).
Such treatment may relieve the pancreatic beta-cells of metabolic demands and thus induce a state of “beta-cell rest”. This quiescent state may be associated with diminished expression of many islet factors, including those that may serve as potential autoantigens at the cell surface (Aaen et al. (1990) Diabetes 39, 697-701; Kämpe et al. (1989) Diabetes 38, 1326-1328). Non-specific immunostimulation caused by cytokine (Jacob et al. (1990) Proc. Natl. Acad. Sci. USA 87, 968
Dyrberg Thomas
Worsaae Anne
Celsa Bennett
Green, Esq. Reza
Gregg, Esq. Valeta A.
Novo Nordisk A S
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