MXPA06007178A - Anti-cd52 antibody treatment for diabetes - Google Patents

Abstract

The present invention provides for the prevention and/or treatment of Type 1 diabetes mellitus with CD52 specific antibodies, e.g. CAMPATH-1H.

Description

ANTI-CD52 ANTIBODY TREATMENT FOR DIABETES Field of the Invention The present invention relates to the use of CD52 specific antibodies in the prevention and / or treatment of Type 1 diabetes mellitus.

BACKGROUND OF THE INVENTION Type 1 diabetes mellitus (insulin-dependent diabetes mellitus; I DDM) is a chronic, organ-specific autoimmune disease resulting from the selective destruction of insulin producing Islet ß cells in the pancreas. In humans, progress in diagnosing the disease to complete the complete destruction of all ß-islet cells in the pancreas typically takes several years (Wucherpennig &Eisenbarth, 2001). This stage of the disease has been referred to as insulinitis. Anti-islet autoimmunity can begin at an early stage in life. Antibodies to multiple antigens. of β-islet cell, such as glutamic acid decarboxylase (eg, GAD65), ICA512 (IA-2) and insulin are produced and can be detected in the blood several years prior to the onset of IDDM. Normally, insulin antibodies appear first, but not always. The presence of multiple anti-islet autoantibodies indicates a high risk of developing diabetes. During the period of insulinitis, there is a progressive loss of β-islet cells, loss of insulin secretion and hyperglycemia. The loss of β-islet cells and insulin secretion produce adverse metabolic changes that include an inability to control blood glucose. Although the etiology of I DDM is unknown, current research indicates that the development of type 1 diabetes is under polygenic control, with major histocompatibility class II (MHC) genes that play an important role in resistance or susceptibility to disease (Todd, 1997). Based on the immunohistochemical analysis of the diabetic pancreas in the NOD mouse and BB rat, it is believed that the disease is mediated by the subset of T 1 helper (Th 1) T lymphocytes and those dendritic cells, macrophages, natural killer (NK) cells , and B lymphocytes accumulate in the site of cell destruction and may play a role in the development of the disease (Ion &Jun, 2001). In animal models of IDDM, pro-inflammatory cytokines such as interferon-gamma (I FN-?), Tumor necrosis factor alpha (TNF-a) and Interleukin 1 (I L-1) have been shown to exacerbate the adverse effects of the illness. Antibodies to island cell antigens such as insulin, glutamic acid decarboxylase (GAD), and ia-2 molecule similar to tyrosine phosphatase, can be detected in pre-diabetic mice and humans and are considered a marker of β-cell destruction in course. These autoantibodies are currently used to identify individuals predisposed to the development of IDDM. Based on experiments with animal models of IDDM, two checkpoints have been identified in the pathogenesis of IDDM (Andre et al., 1996). Verification point 1 controls the onset of insulinitis and checkpoint 2 controls the change of insulinitis to I DDM It is interesting to note that in these animal models that extensive and active insulinitis may persist for long periods of time before the IDDM occurs. . In this way, the therapeutic intervention that suppresses the insulinitis phase of the disease could delay or prevent diabetes and have an important impact on the decrease of the disease.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a method for the treatment or prevention of diabetes, comprising administering an effective amount of an anti-CD52 antibody to a patient in need of such treatment. In some embodiments, the anti-CD52 antibody is CAMPATH-1 H.

DETAILED DESCRIPTION OF THE INVENTION A. Specific Antibodies CD52 The CD52 antigen (CAM PATH-1) is a glycoprotein expressed in lymphocytes., monocytes, macrophages, NK cells and tissues of the male reproductive system (Hale et al., 1990). Anti-CD52 antibodies bind to all lymphocytes, a majority of monocytes, macrophages and NK cells, and a subpopulation of granulocytes. CAMPATH-1 M is a rat monoclonal IgM antibody that has been used extensively to deplete T cells in bone marrow cultures before transplantation. CAMPATH-1 H is a humanized monoclonal antibody and is approved for the treatment of chronic B cell lymphocytic leukemia in patients who have been treated with alkylating agents and for whom fludarabine therapy has failed. CAMPATH-1 H is distributed as CAMPATH® (Alemtuzumab) in the US (Berlex) and MABCAMPATH ™ in Europe (Schering AG) The infusion of CAMPATH-1 H results in a rapid drop in lymphocyte and monocyte counts during the first hours post-treatment and a prolonged lymphopenia that is presents for more than 2 years. B. Formulations and Administration The pharmaceutical compositions according to the present invention are prepared in a conventional manner, comprising substances which are commonly used in pharmaceuticals, for example, Remington's Pharmaceutical Sciences, 1st 8th Edition, Mack Publishing Company (1990), including excipients , vehicles, adjuvants and regulators. The compositions can be administered, for example, parenterally, enterically, orally, intramuscularly, subcutaneously, intravenously, aerosolized or other routes useful to achieve an effect. For example, anti-CD52 antibodies, preferably CAMPATH-1 H, can be given intravenously (Coles et al., 1999; Moreau et al., 1996; Moreau et al., 1994), all incorporated herein. for reference) and subcutaneously (Schnitzer et al., 1997; Bowen et al., 1997, both incorporated herein by reference). Conventional excipients include pharmaceutically acceptable organic and inorganic carrier substances for parenteral, enteral or topical application that do not deleteriously react with the agents. Pharmaceutically suitable adjuvants include, but are not limited to, water, salt solutions, alcohols, gum arabic, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, monoglycerides and diglycerides of fatty acid, fatty acid esters of pentaerythritol, hydroxy-methylcellulose, polyvinyl pyrrolidone, cyclodextrins, etc. The pharmaceutical preparations can be sterilized and, if desired, mixed with stabilizers, wetting agents, emulsifiers, salts for influencing the osmotic pressure, regulators, colorants, flavors and / or aromatic substances, etc. , that do not react in a harmful way with the active compounds. For parenteral application, sterile injectable solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, including suppositories, are particularly suitable. The vials are convenient unit doses. The compositions may also be formulated in an aqueous solution, optionally with the addition of additives common in galenics, eg, regulators; electrolytes such as sodium chloride; antioxidants such as ascorbic acid; adjuvants, for example, methylcellulose, lactose and mannitol and / or surfactants, for example, lecithins and Tweens and / or aromatic substances for flavoring, for example, ethereal oils. The dose of a cheesy anti-CD52 antibody, preferably CAMPATH-1 H, can vary with the condition of the patient and will generally be in the range of about 10 to about 150 mg for an adult patient, normally administered for a period of time from 1 Up to approximately 20 days. The course of treatment may be given once or may be repeated at intervals of approximately 3 months, or approximately six months, or approximately 9 months, or approximately 12 months, or approximately 18 months or approximately 24 months, the number of courses of treatment depending on the medical status of the patient, including, but not limited to, the patient's symptoms and the degree and persistence of lymphopenia. In some embodiments of the present invention, dose schedules suitably used in a clinical study are at a low dose level of a total of 60 mg IV for 5 consecutive days (12 mg / day) and a higher dose level of a total of 1 20 mg IV for 5 consecutive days (24 mg / day). Retreatment can be given at 24 months and 48 months at a low dose level of a total of 36 mg IV for 3 consecutive days (12 mg / day) and at a dose level greater than a total of 72 mg IV for 3 consecutive days (24 mg / day). The first course of treatment with CAMPATH-1 H has been. assocd with a reversible exacerbation of existing neurological symptoms and the activation of asymptomatic lesions caused by cytokine antibody-induced release (Moreau et al., 1992a).; Wing I went to. , nineteen ninety six). This cytosine release syndrome can be prevented by pretreatment with methylprednisolone (Coles et al., 1999, incorporated herein by reference).

EXAMPLES OF THE INVENTION A. Clinical Evaluation - Prevention Trials aimed at preventing the progression of pre-diabetic individuals preferably recruit the first-degree relatives of individuals diagnosed with I DDM, since the risk of manifesting clinical DDM is at least 10 times higher than the general population (Tarn et al., 1988). The eligibility requirements also include patients being positive for cell island antibodies (ICA), for example, if patients exhibit ICA's of > . 20 units of the Juvenile Diabetes Foundation (JDF) in the serum. The ICA is determined by indirect immunofluorescence in human pancreas cryostat sections (Lampeter et al., 1994, Becker et al., 1990). Other useful surrogate markets indicating the destructive process of β-cells include glutamic acid decarboxylase (GAD) and transmembrane protein tyrosine phosphatase (1A-2) and may be useful in the selection of the general population (Pozzilli et al., 2001). The combination of GAD and IA-2 antibodies has a greater specificity for IDDM, especially in subjects over 10 years of age (Savola et al., 1997) and has a predictive value for IDDM in relatives of fifth degree similar to ICA. (Kulmala eí a /., 1998). Age also influences the progress of clinical IDDM, with greater speed in younger subjects at risk (Bingley, 1996). Thus, the eligibility requirements may be of relatives of patients aged 3-14 years with I DDM positive for ICA or positive for GAD and IA-2, in whom a diabetic condition has been excluded by a test of oral glucose Individuals are appropriately assigned to treatment or control groups in a blind manner, for example, with the use of a randomized algorithm per permuted block. Line-based investigations and follow-up of standard, hematological and biochemical markers are carried out. Metabolic examination may include intravenous glucose tolerance test, oral glucose tolerance test, glycosylated hemoglobin, HbAi and HbA1 c. Follow-up examinations can be adequately experienced at 6 weeks, 6 months and every 6 months thereafter for an adequate time, for example 3 or 5 years. Cumulative diabetes incidents can be estimated by using Kaplan-Meyer curves (Kalbfleisch &Prentice, 1980).

B. Clinical Evaluation - Treatment / Reversal Studies similar to those conducted in pre-diabetic individuals are experienced in newly diagnosed IDDM patients. Patients continue with insulin therapy during the study period. Serum C-peptide levels can also be measured (Herold et al., 2002). The present invention has been shown both by description and by examples. The examples are for exemplification only and can not be considered as a limit to the scope of the invention. One of ordinary skill in the art will provide equivalences to the inventive process described by the following claims which are within the scope and spirit of the claimed invention.

REFERENCES The following references, to the extent that they provide exemplary procedures or other supplementary details for those set forth herein, are specifically incorporated herein by reference. Andre went to. , "Checkpoints in the progress of autoimmune disease: Lessons from diabetes models", Proc: Nati Acad Sci USA, 93: 2260-2263, 1996. Becker et al. , Identification of the pre-diabetic state in type I diabetes ", J. Autoimmun., 3: 639-642, 1 990. Bingley," Interactions of mature islet cell antibodies, insulin auto-antibodies and insulin response. first phase in the prediction of the risk of progress to IDDM in ICA + relatives; the ICARUS data set ", Diabetes, 45: 1720-1728, 1996. Bowen et al., "CAMPATH-1 H subcutaneous in lymphocytic and chronic B-prolymphocytic leukemia, resistant to fludarabine / recidivism", Br. J. Hematol. , 96: 617-9, 1997. Coles eí al. , "The treatment of monoclonal antibody exposes three mechanisms underlying the clinical course of multiple sclerosis," Ann. Neurol. , 46: 296-304, 1999. Hale ei a /. , "CAMPATH-1 Antigen (CDw52), Tissue Antigens" 35: 1 18-27, 1 990. Herold et al. , "Monoclonal anti-CD3 antibody in type I diabetes mellitus of new onset", N. Engl. J. Med., 346: 1692-1698, 2002. Kalbfleisch & amp;; Prentice, "Statistical analysis of failure time data," New Cork, John Wiley, 1980. Kilo, "Value of glucose control in the prevention of complications of diabetes," Am J Med 79 (compl 2B): 33 -37, 1 985. Kulmala eí al. , Prediction of insulin-dependent diabetes mellitus in relatives of children with diabetes - a population-based study, "J. Clin. Invest., 101: 327-336, 1998. Lampeter et al., Inflammatory islet damage in patients that have HLA-DR3 and / or DR4 haplotypes that do not lead to islet autoimmunity ", Diabetología, 35: 471 -475, 1994. Moreau eí a /. , "Preliminary evidence of magnetic resonance imaging for reduction in disease activity after depletion of lymphocytes in multiple sclerosis"; Lancet, 344: 298-301, 1994. Moreau eí al. , "CAMPATH-1 H in multiple sclerosis", Multiple Sclerosis, 1: 357-65, 1996. Moreau eí al. , "Transient increase in symptoms associated with cytosine release in patients with multiple sclerosis", Brain, 1 1 9: 225-37, 1996a. I went to al. , "Biochemical markers of type I diabetes: clinical use", Scand. J. Clin. Invest. , 61 (item 235): 38-44, 2001. Savola eí al. , "Antibodies IA-2 in relation to other autoantibodies and markers of genetic risk in children with recent onset of IDDM", Diabetología, 40 (compl .. 1): A70 (abstract). Immune Schnitzer et al., "Subcutaneous Administration of CAMPATH-1H: Clinical and Biological Results", J. Rheumatol., 24: 1031-6, 1997. Tarn. al., "Prediction of Insulin Dependent Diabetes", Lancet, 1 (8590): 845-850, 1988. Todd, "Genetics of type 1 diabetes", Pathol Biol Paris 45: 219-227, 1997. Toms & Powrie, "Control of intestinal inflammation by regulatory T cells". Microbes Infect, 3: 929-935, 2001. Wing ei al., "Mechanism of first-dose cytosine release syndrome by CAMPATH 1-H: involvement of CD16 (Fc? Rlll) and CD11a / CD18 (LFA-1) in NK cells ", J. Clin. Invest., 12: 2819-26, 1996. Wucherpennig & Eisenbarth, "Type 1 Diabetes", Nature Immunol.2 (9): 767-768, 2001. Yoon & Jun, "Cellular and molecular pathogenic mechanisms of diabetes mellitus dependent on Insulin", Ann New and Acad. Svi: 928: 200-211, 2001).

Claims (4)

1. CLAIMS 1. A method for the prevention of Type 1 diabetes mellitus in a prediabetic human subject, characterized in that it comprises the administration to said subject of an effective amount of an anti-CD52 antibody.
2. 2. The method according to claim 1, characterized in that said anti-CD52 antibody is CAMPATH-1 H.
3. 3. A method for the treatment of diabetes mellitus Type 1 in a human subject suffering from said disease, characterized in that it comprises administration to said subject of an effective amount of an anti-CD52 antibody.
4. 4. The method according to claim 1, characterized in that said anti-CD52 antibodies is CAMPATH-1 H.