WO2009145831A1

WO2009145831A1 - Treatment of the idiopathic nephrotic syndrome spectrum diseases using basiliximab

Info

Publication number: WO2009145831A1
Application number: PCT/US2009/002049
Authority: WO
Inventors: Glen H. Bock
Original assignee: Geisinger Clinic
Current assignee: Geisinger Clinic
Priority date: 2008-04-02
Filing date: 2009-04-02
Publication date: 2009-12-03
Anticipated expiration: 2010-10-02

Abstract

Methods for treating Idiopathic Nephrotic Syndrome Spectrum (INSS) diseases using antibodies to the IL-2 receptor (anti-IL-2r antibodies) of T cells, such as basiliximab are described. The methods may be used for treating the broad spectrum of INSS diseases in both children and adults.

Description

Treatment of the Idiopathic Nephrotic Syndrome Spectrum Diseases

Using Basiliximab Statement of Priority

[0001] This application claims priority to U.S. Provisional Application No. 61/041,741, filed April 2, 2008, whose disclosure is hereby incorporated by reference herein.

Field of the Invention

[0002] The present invention relates to methods of treatment of Idiopathic Nephrotic Spectrum diseases in both children and adults. The methods of treatment of the present invention involve administering a chimeric monoclonal anti-interleukin-2 receptor antibody (Basiliximab) to a patient having an Idiopathic Nephrotic Spectrum disease. Background of the Invention

[0003] Idiopathic nephrotic syndrome (INS) accounts for 90 percent of all cases of nephrotic syndrome occurring in children <10 years of age. In older children and adults, 50% and 10-15%, respectively, of all cases of nephrotic syndrome are due to INS. Oral corticosteroids (primarily prednisone) have been used as the initial form of therapy for INS for more than 50 years. When INS patients are unresponsive to steroid therapy, when remission cannot be sustained without continuous therapy, or in the event of serious corticosteroid drug side effects, a number of alternative immunotherapeutic agents are often used. These include cyclophosphamide, chlorambucil, cyclosporine, tacrolimus, levamisole, and mycophenolate mofitil. However, the clinical response to these agents is frequently suboptimal and the long-term benefits limited. At the same time, treatment- resistant INS appears to be on the rise, resulting in increased risks of chronic nephrotic syndrome and end-stage renal disease.

[0004] Although a specific mechanism underlying INSS in humans has remained elusive despite decades of research, there are considerable direct and indirect data implicating a T-cell role in its pathophysiology. Despite the incompletely delineated pathophysiology, new therapeutic possibilities have emerged with the development of monoclonal antibodies that allow specifically-targeted T-cell immunotherapy. Several of these agents, while routinely used for kidney transplant induction therapy, have not been systematically evaluated nor used in a targeted fashion in those patients with recurrence of their nephrotic syndrome after transplantation. To date, the only monoclonal antibody that has been used in INS patients who have not undergone kidney transplantation is rituximab which is an anti-CD20 antibody that targets B-cells.

[0005] Unremitting, INSS may have significant clinical consequences. Chronically nephrotic patients, both children and adults, are at increased risk for serious bacterial infections, spontaneous vascular thromboses, the consequences of severe uncontrolled hyperlipidemia, complications and side effects of chronic immunotherapy, and progression to chronic renal failure. There also is substantial risk of disease recurrence in those patients undergoing transplantation. Clearly, alternative and effective treatments are needed both for steroid-dependent and steroid-resistant cases. Summary of the Invention

[0006] It is an object of the present invention to provide a method for treating a patient having an idiopathic nephrotic syndrome spectrum (INSS) disease by administering to the patient an effective amount of a monoclonal antibody (mab) that specifically binds to the IL-2 receptor (IL-2r) (CD25) and blocks receptor- activation, such as basiliximab. The administration of the anti -IL-2r mab may be done alone or in combination with other agents used in treating INSS diseases.

[0007] It is a further object of the present invention to provide a method for treating a patient having an INSS disease by administering an anti-IL-2r antibody multiple times over a determined dosing period. The dosing period may be a few days to several weeks or months, the dose may be given two or more times during the dosing period. In some embodiments of the present invention, the initial dose given on day 1 of the dosing period may be larger than the subsequent doses given during the period. However, it is also contemplated that all of the doses in the dosing period be the same amount. [0008] It is a still further object of the present invention to provide a method for determining an amount of anti -IL-2r mab effective in treating an idiopathic nephrotic syndrome. This method involves providing a patient having idiopathic nephrotic syndrome; administering to the patient an amount of anti -IL-2r mab; and assessing the degree and duration of IL-2-receptor saturation; wherein the effectiveness of IL-2 receptor saturation is a determinant of the dose of anti -IL-2r mab required by the patient. [0009] It is yet a further object of the present invention to provide a method for determining an individual dose of anti -IL-2r mab effective in treating an idiopathic nephrotic syndrome disease. This method involves providing a patient having a» idiopathic nephrotic syndrome disease; administering to the patient an amount of anti -IL- 2r mab; and determining the fractional excretion of IgG; wherein the fractional excretion of IgG provides guidance about the dose and/or frequency of administration of the anti- IL-2r mab required by the patient. Brief Description of the Drawings

[0010] Figure 1 is a plot of both body weight and serum albumin concentration versus days after initial basiliximab treatment for the patient of the Example.

[0011] Figure 2 is a plot of both serum albumin concentration and the Log of urine protein / creatine concentration versus months of treatment for the patient of the

Example.

[0012] Figure 3 is a graph of the serum cholesterol for each treatment period for the patient of the Example.

[0013] Figure 4 is a graph of vascular permeability in nephrotic syndrome before and after corticosteroid treatment based on data from Rostoker et al. (4).

Detailed Description of the Invention

[0014] The present invention provides methods for the treatment of Idiopathic

Nephrotic Syndrom Spectrum (INSS) diseases through the administration of basiliximab, either alone of in combination with other agents. The present invention also provides methods for determining a dose of basiliximab for administering to a patient having an

INSS disease. Additionally, the present invention provides methods for determining the success of a treating an INSS disease using basiliximab.

[0015] The treatment methods of the present invention involve the administering of basiliximab or similar antibodies. Basiliximab is a chimeric mouse-human monoclonal

IgG antibody to the Interleukin-2 receptor α-chain (CD25, anti-IL-2r) that is expressed on

T cells. Basiliximab is sold under the trade name SIMULECT®. It is also contemplated that other antibodies to the IL-2r receptor may be used in the present invention, including unmodified, chimeric and humanized antibodies from other animal sources. It is further contemplated that engineered antibodies against the IL-2r receptor, e.g. a CD25 blocking antibody, may be used within the scope of the present invention. [0016] Any of the known INSS diseases are contemplated as being treatable by the methods of the present invention. Those diseases include, but are not limited to, minimal change disease, focal segmental glomerulosclerosis, mesangial proliferative, membrano proliferative glomerulonephritis, membranous nephropathy, nephrotic syndrome (with or without IgM), and CIq nephropathy. It is also contemplated that the methods of the present invention can be used for the treatment of other nephrotic syndromes, including non-idiopathic nephrotic syndromes. It is still further contemplated that the methods of the present invention may be used for treating patients with other types of renal glomerular diseases

[0017] INSS diseases can be diagnosed using methods well known in the art. Patients with these diseases may show puffiness around the eyes, edema over the legs, and fluid in the pleural and peritoneal cavities. Some patients may also have foamy urine due to proteinuria. Typical investigations undertaken to diagnose INSS disease may include analysis of urine for proteinuria, with greater than 40 mg/m /hour an indication of the presence of a nephrotic syndrome. Other investigations may include a metabolic panel to detect hypoalbuminemia, and hypochloresterolemia and an analysis of electrolytes, urea and creatinine to evaluate renal function, hi certain circumstances, other tests include complement C3 and C4 and certain autoantibodies. In some cases, a biopsy of the kidney may be indicated if diagnosis is unclear. Additional information on diagnosis of INSS diseases, can be found in the Genitourinary Disorders section of the Merck Manual of Diagnosis and Therapy, which is hereby incorporated by reference herein. (5)

[0018] The methods of treatment of the present invention may be used alone or in conjunction with other traditional methods of treating INSS diseases. Traditional methods of treating INSS diseases include treatment with corticosteroids, such as prednisone. Other agents used in the treatment of INSS diseases include intravenous methylprednisone, cyclosporine, cyclophosphamide, chlorambucil, cyclosporine, tacrolimus, sirolimus, levamisole, and mycophenolate mofetil. If an anti -IL-2r mab is used in conjunction with another agent, the other agent may be administered in its usual amounts, or the amount of the agent administered may be reduced.

[0019] In certain embodiments of the invention, an anti -IL-2r mab is used to treat an

INSS disease from the initial diagnosis. In these embodiments, the anti -IL-2r mab may be administered alone or in conjunction with traditional treatments. In other embodiments an anti -IL-2r mab may be used to treat an INSS disease that has proved resistant to other treatments, such as a corticosteroid refractory form of an INSS disease.

Typically, these patients have failed to achieve remission of the disease through the use of other agents.

[0020] In still further embodiments, the anti -IL-2r mab may be administered in the setting of immunosuppressive drug dependency in order to sustain remission. It may also be administered for treatment of recurrent primary focal segmental glomerulosclerosis

(FSGS) after kidney transplantation.

[0021] The anti -IL-2r mab may be administered in a wide variety of dosages over a variety of dosing schedules. Typically, a dosage of between 5 mg and 60 mg of anti -IL- 2r mab is given, with a range of 20 mg to 40 mg being preferred. In one embodiment, the anti -IL-2r mab may be administered to the patient on a 30 day dosing schedule, with administrations on days 1, 4, 7, 14 and 28. In another embodiment, a dosing schedule of two weeks may be used, with administrations on days 1, 4 and 14. It is also contemplated that dosing schedules can be extended much longer, including and beyond 100 days from the initial dose. However, it will be apparent to one of skill in the art that other dosage schedules may be used without departing from the scope of the present invention, including longer or shorter schedules or schedules with more or less frequent dosing. In some embodiments of the invention, the amount of the dose may be varied over the course of the schedule. This may include dosing where the initial dose is a larger amount (e.g. 40 mg) and subsequent doses are smaller amounts (e.g. 20 mg). [0022] It is also contemplated that more than one dosing schedule period may be administered to a patient with a period of no anti -IL-2r mab administration between dosing periods. For example, a first dosing schedule may be completed, and the patient may then not be treated with anti -IL-2r mab for a period of several weeks or months. This break in dosing may be because the patient has gone into remission for the INSS disease, or it may be that the patient still presents the disease during this break in dosing. It is further contemplated that two, three, four or more dosage periods may be used with breaks in between.

[0023] The methods of treatment of the present invention are advantageous in that they may achieve a sustained disease remission in patients unresponsive to other therapies. Additionally, the treatment methods of the present invention may be an alternative form of primary therapy either to avoid the initial side effects of prolonged corticosteroid treatment, or in those patients with contraindications to steroid therapy. The methods of treatment also avoid the recognized, often severe side effects and potential complications of the currently used immunotherapies. [0024] In addition, the important observation described above regarding the resolution of peripheral edema/ascites preceding improvement of hypoalbuminemia (and hence plasma oncotic pressure) following anti -IL-2r mab treatment serves as a potentially useful model for human studies of the mechanisms of nephrotic edema formation.

[0025] In other embodiments of the present invention, methods are provided for determining a dosage of anti -IL-2r mab for treatment of INSS diseases. Currently, there are no guidelines for adjustment of dose when there is coexistent proteinuria, and the little existing data indicate that without dose adjustments, standard treatment protocols will be suboptimal.

[0026] Flow cytometry is a useful, established and available method for determining biological and pharmacokinetic properties of IL-2 receptor blockade by anti -IL-2r mab. The methods of the present invention contemplate using flow cytometry to measure the proportion of CD3+ lymphocytes that are CD25+ (CD25 = IL-2 receptor alpha chain = tac receptor = basiliximab target). If cell receptor binding of the indicator anti -IL-2r mab is inhibited by the pre-existent binding of anti -IL-2r mab, serial measurements of the percent and duration of IL-2 receptor saturation after treatment can be determined. The information derived from this is potentially relevant to the treatment of proteinuric and nephrotic conditions in general and does not currently exist. [0027] Native, chimeric and humanized monoclonal IgG antibodies should undergo renal clearance in a manner similar to, if not indistinguishable from, the renal clearance of circulating native IgG antibody. Depending on the underlying cause, the profile of protein losses in nephrotic and proteinuric conditions (including INSS diseases) can vary considerably.

[0028] The measurement of IgG concentrations in serum and urine are widely available clinical laboratory procedures. Likewise, creatinine concentration measurements in these fluids are standard clinical lab tests. The easily calculated fractional urine excretion of IgG can be an index of IgG losses into the urine in individual patients. By contrast, flow cytometry for these purposes is not readily available. The methods of the present invention provide for determining the correlation between flow cytometry determined dosing guidelines and IgG fractional excretion. These methods are potentially applicable to other monoclonal antibody clinical products, in addition to basiliximab.

[0029] Fractional excretion of IgG is calculated like other fractional excretions:

[0030] FEIgG = purine /IgGplasma ^₀₀

Cruήne I Crplasma

[0031] Where FEIgG = fractional IgG excretion;

[0032] [IgGxxx] = concentration of IgG in g/dL; and

[0033] [Crxxx] = concentration of creatine in mg/dL.

[0034] After a correlation between fractional urine excretion and flow cytometry data is determined using statistical methods known in the art, the correlation could be used to determine dosing based on IgG fractional excretion guidelines. An indication of the percent and duration of receptor saturation can be used for adjusting dosage of an anti - IL-2r mab. If the receptor saturation is determined to be too low, the dosage of anti-IL-2r antibody can be increased. Conversely, if there is excessively high or prolonged receptor saturation, the dosage may be reduced.

[0035] It should be apparent to one of skill in the art that there are other variations on the methods of the present invention that are not described explicitly herein which fall within the scope of the invention as claimed below. The Examples set forth below are informational, and are not meant to be limiting, but instead to describe embodiments of the present invention.

Example

Treatment of Multi-Drug Resistant Focal Segmental Glomerulosclerosis (FSGS) With

Basiliximab

Introduction

[0036] Clinical

[0037] The idiopathic nephrotic syndrome (INS) spectrum includes minimal change disease, mesangial proliferative nephrotic syndrome, and focal segmental glomerulosclerosis (FSGS). While INS accounts for the majority of cases of nephrotic syndrome in children, it can first appear at any age. Remission resulting from corticosteroid (CS) treatment also correlates with long-term outcome. Alternative therapies, including cytotoxic and antiproliferative agents and calcineurin inhibitors, are most often used when CS non-response or cumulative toxicity occurs. The long-term risk:benefit of these agents is uncertain.

[0038] Pathogenesis [0039] There is considerable direct and indirect data implicating a role for T cell activation, including Interleukin-2 (IL-2) induced T cell activation, in the pathogenesis of INS.(l) IL-2 induced T cell proliferation is mediated by its cell-surface receptor and increased IL-2 receptor (CD25) expression has been demonstrated in INS during relapse. (2) Since anti-IL-2 receptor monoclonal antibodies can abrogate IL-2 induced T cell proliferation, we considered their potential benefit in INS. As such, a multi-drug resistant INS patient was treated with the chimeric anti-IL2 receptor monoclonal antibody, basiliximab (BIx). Patient Characteristics

[0040] The patient is currently a 15 year old Caucasian male. The onset of nephrotic syndrome (NS) was at age 14 months. NS was initially corticosteroid responsive, subsequently became dependent, then resistant. First kidney biopsy was at age 20 mo: Juxtamedullary FSGS; no significant tubulointerstitial fibrosis. [0041] The patient had multiple drug treatment failures with prednisone, cyclophosphamide, cyclosporine, mycophenolate mofetil and tactrolimus. The patient had a number of complications, including severe hyperlipidemia, being moderately Cushingoid, moderate to severe obesity, statural growth delay and multiple hospitalizations for episodes of anasarca/ascites

[0042] Second kidney biopsy was at age 12 years: FSGS with IgM nephropathy; no significant tubulointerstitial fibrosis. He received 2 series of basiliximab treatment, approximately 6 months apart, beginning at age 14 years. [0043] The treatment protocol is shown in Table 1 Table 1

[0044] Results

[0045] Early Response (Figure 1)

[0046] Diuresis

[0047] Within days of the 1st BIx dose, the patient had a spontaneous increase of urine output such that he lost approximately 7.6kg, or about 16%, of his body weight between days 0 and 14. Diuresis and weight loss continued with resultant complete resolution of edema and ascites within about 3 weeks.

[0048] Serum Albumin

[0049] Serum albumin initially remained at a very low level, followed by an upwards trend beginning between days 10 and 14 (Figure 1). This was consistent with the observation of >50% reduction of proteinuria (Figure 2) that was also seen by Day 10.

[0050] Importantly, the onset of diuresis clearly preceded the subsequent increase of serum albumin by at least 1 week. Nephrotic-range proteinuria was also observed during this early time period.

[0051 ] Treatment Response (Figures 2 & 3)

[0052] Period 1 [0053] During the 6 months following the initial BIx treatment course (Period 1), there was a substantial reduction of proteinuria (Figure 2), based on first-morning urine protein: creatinine ratios and 24-hour urine samples. The proteinxreatinine ratio (mg/mg) decreased from 9.7 ± 2.4 (x ± ISD) during the 12 months prior to the first dose of basiliximab (Period 0) to 5.5 ± 4.2 during Period 1.

[0054] Serum albumin generally increased through Period 1 and reached the lower limit of normal by about 22 weeks. Figure 3 compares fasting serum total cholesterol during the treatment intervals. The partial improvement of INS during Period 1 was reflected in the improved but still elevated serum cholesterol levels averaging 243 ± 56 mg/dL for Period 1 vs 422 ± 184 prior to treatment (Period 0).

[0055] Period 2

[0056] A second course of BIx was given in view of the preceding partial response and possible under-treatment during Period 1 (see Summary and Conclusions). Figs 2 and

3 show the subsequent rapid improvement and normalization of the nephrotic syndrome indices. The proteinxreatinine ratio decreased to 0.65 ± 0.16 and serum cholesterol levels improved to 176 ± 12. The treatment was tolerated without incident and HAMA antibodies were not detected. Kidney function continues to be normal, and the patient remains clinically well.

[0057] TREATMENT PERIODS

[0058] 0: Interval prior to BIx treatment

[0059] 1 : Following 1 st course BIx

[0060] 2: Following 2nd course BIx

Summary and Conclusions [0061] Remission occurred in a multidrug-resistant patient with INS/FSGS after treatment with basiliximab combined with prednisone and mycophenolate mofetil. The response following treatment with this protocol is encouraging. Although limited clinical observations of this sort must be interpreted cautiously, this patient's prior clinical course makes the case for a cause-effect more credible.

[0062] It is extremely likely that the presence of high-level proteinuria foreshortens the duration of action of basiliximab (3). This supposition led to an empirical increase of the dose and duration of therapy in our patient. It is essential to further clarify the optimal basiliximab treatment dose and duration in future studies of its use in nephrotic disorders. [0063] The onset of the diuresis in this patient prior to any detectable change of serum albumin supports a role for altered systemic capillary permeability in edema formation in INS. This is consistent with recent observations suggesting abnormal systemic vascular permeability in INS (4) (see Figure 4). Our observations suggest that disturbances of both permeability and the transcapillary colloid-osmotic pressure gradient play roles in INS. In addition to the possible therapeutic benefit, the use of basiliximab in INS could represent a human model to further investigate the pathophysiology of edema formation in nephrotic states.

Additional Information About the Treatment Studies

[0064] Among those pediatric nephrology INS patients at Geisinger with multidrug-resistant disease and intractable nephrotic syndrome, two patients and their parents were offered off-label treatment with basiliximab (SIMULECT®). The rationale for using an anti IL-2 receptor antibody is based on the evidence cited above as well as the numerous observations that clinical settings where T-cell activation occurs are traditionally associated with relapse of INS. Also, increased expression of CD25, and increased blood and urine soluble IL-2 receptor concentrations have been observed in INS patients. The parents of these patients were required to give consent for this off label treatment, and they were fully informed about the nature and potential risks of this therapy.

[0065] PATIENT SUMMARIES

[0066] The two patients were treated with basiliximab, three doses each (see below). Basic clinical characteristics are listed in Table 2.

Table 2

Patient I Patient 2

Current age 10 years 14 years

Gender Male Male

Age of disease onset 34 months 14 months

Kidney biopsy FSGS FSGS

Serum creatinine (latest) 0.9 mgtøL 0.7 mg/dL

[0067] Both patients initially had corticosteroid-responsive nephrotic syndrome, but subsequently they clearly could not achieve or sustain a remission with corticosteroids (prednisoione/prednisone or methylprednisolone), cyclophosphamide, cyclosporine, or mycophenolate mofϊtil. In addition, Patient 2 underwent an unsuccessful treatment course using tacrolimus. Both patients have developed serious complications of their prior medical therapies, including cataracts (1), hyperlipidemia (2), hypertension (1), Cushing's syndrome (2), obesity (2), gingival hypertrophy (1), and linear growth delay (2). The basiliximab treatment regimen details are listed in Table 3.

Table 3 Patient I Patient 2 basiliximab 20 mg IV (Days 0, 4, 14) 0.65 mg/kg/dose 0.43 mg/kg/dose mechylprednisolone IV (Days 0, I } 5.6 mg/kg/day 5 mg/kg/day prednisone I mg/kg/day PO (beginning day 2) 30 mg daily 45 mg daily mycophenolate mofitil PO q I2h beginning day 0 730 mg/mVdose 551 mg/mVdose

[0068] No other treatment changes occurred during the observation period and the treatment was well tolerated in both patients with no discemable adverse effects. [0069] Patient 1 experienced an increased urine output and lost approximately 4.1 kg in weight between days 0 and 14 and had no remaining signs of edema/ascites at the day 14 evaluation. The patient's mother reported an additional 2 kg weight loss within 2 days of the 3rd basiliximab dose. Interestingly, the degree of proteinuria diminished considerably, but did not normalize. The urine protein:creatinine ratio from 24-hour urine collections decreased more than 50% from 1 1.0 on day 0 to 4.6 on day 31 although the serum albumin remained in pre-treatment 1.5-1.9 g/dL range.

[0070] Patient 2 also had an increased urine output and lost approximately 7.6kg, or about 17%, of his body weight between days 0 and 14. The patient's mother reported another 4.5kg of weight loss within about 1 week of the 3rd basiliximab dose. He also had no sign of edema or ascites at follow up exams. There was a substantial reduction of proteinuria, based on a urine proteinxreatinine ratio from 24-hour urine collections. The proteinxreatinine ratio decreased dramatically from 12.5 immediately prior to the first dose of basiliximab to a value of 2.4 on day 57. Serum albumin gradually increased to 2.7 g/dL, the highest value in more than 2 years and well above the pre-treatment level of 1.5 g/dL on day 0 to 2.7g/dL on Day #57. [0071] By 8 - 12 weeks the degree of proteinuria gradually increased in both patients although Patient 2 remains edema-free. [0072] Comments

[0073] The initial clinical course following treatment with the basiliximab protocol is extremely encouraging. Both patients tolerated the therapy with no adverse effects, and experienced a dramatic diuresis within a week of the initiation of therapy and completely lost all traces of edema and ascites. Although limited clinical observations of this sort must be interpreted cautiously, the prior clinical courses of these patients and the similarities of their dramatic clinical responses to treatment make the case for cause/effect more credible. If our treatment approach can be verified in a systematically structured and controlled setting, there is the potential to open novel new avenues of treatment and clinical investigation. References

1. Cunard R and Kelly CJ. T Cells and Minimal Change Disease. J Am Soc Nephrol 2002;13:1409-1411.

2. Bock GH, Ongkingco JR, Patterson LT, Ruley J, Schroepfer LR, Nelson DL. Serum and urine soluble interleukin-2 receptor in idiopathic nephrotic syndrome. Pediatr Nephrol 1993;7:523-8.

3. Nagai T, Goto Y, Haba T, Uchida K. The effect of urinary protein excretion in post-renal transplant recurrent nephrotic syndrome on basiliximab pharmacokinetics and pharmacodynamics in a pediatric patient. Transpl Proc 2005;37:879-80.

4. Rostoker G, Behar A, Lagrue G. Vascular hyperpermeability in nephrotic edema. Nephron 2000;85: 194-200.

5. The Merck Manual of Diagnosis and Therapy, 18^th Edition, Robert S. Porter, MD, Editor, 2006, Merck Research Laboratories. 6. Differential risk of remission and ESRD in childhood FSGS. Gipson DS, Chin H, Presler TP, Jennette C, Ferris ME, Massengill S, Gibson K, Thomas DB. Pediatr Nephrol 21 :344-9, 2006

7. Adult-onset idiopathic nephrotic syndrome associated with Rare diffuse mesangial hyperercellularity. Alexopoulos E, Papagianni A, Stangou M, Pantzaki A₃ Papadimitriou M. Nephrol Dial Transplant. 15(7):981-87, 2000

8. T Cells and Minimal Change Disease. Cunard R and Kelly CJ. J Am Soc Nephrol 13: 1409-141 1, 2002

9. Lymphocyte subpopulations, interleukin-2 and interleukin-2 receptor expression in childhood nephritic syndrome. Hlton SA, Shah V, Byrne MR, Morgan G, Barratt TM, Dillon MJ. Pediatr Nephrol. 8(2): 135-9, 1994

Claims

What is claimed is

1. A method for treating a patient having an idiopathic nephrotic syndrome spectrum disease comprising administering to the patient an amount of an anti-IL-2r antibody effective to treat the disease.

2. The method of claim 1, wherein the anti-IL-2r antibody is administered to the patient in combination with another therapeutic agent.

3. The method of claim 2, wherein the other therapeutic agent is a corticosteroid.

4. The method claim 3, wherein the corticosteroid is prednisone.

5. The method of claim 2, wherein the other therapeutic agent is selected from the group consisting of cyclosporine, cyclophosphamide, chlorambucil, cyclosporine, tacrolimus, sirolimus, levamisole, and mycophenolate mofetil.

6. The method of claim 1, wherein the anti-IL-2r antibody is basiliximab.

7. The method of claim 1, wherein the amount of anti-IL-2r antibody administered is between about 5mg and about 60mg.

8. The method of claim 1, wherein the idiopathic nephrotic syndrome is selected from the group consisting of minimal change disease, focal segmental glomerulosclerosis, mesangial proliferative, membrano proliferative glomerulonephritis and membranous nephropathy.

9. A method for treating a patient having an idiopathic nephrotic syndrome spectrum disease comprising: determining the length of a dosing period; administering to the patient an initial dose of a anti-IL-2r antibody on the first day of the dosing period; administering to the patient one or more subsequent doses of a anti-IL-2r antibody on subsequent days until the end of the dosing period; wherein the sum of the initial and subsequent doses is sufficient to treat the idiopathic nephrotic syndrome.

10. The method of claim 9, wherein the length of the dosing period is 14 days and the total number of doses is four or more.

11. The method of claim 9, wherein the length of the dosing period is 30 days and the total number of doses is four or more.

12. The method of claim 9, wherein the length of the dosing period is 70 days and the total number of doses is four or more.

13. The method of claim 9, wherein the initial dose of the anti-IL-2r antibody and the subsequent doses of the anti-IL-2r antibody are all between about 5mg and about 60mg.

14. The method of claim 9, wherein the initial dose of the anti-IL-2r antibody is about 40mg and the subsequent doses of the anti-IL-2r antibody are about 20mg.

15. The method of claim 9, wherein the patient is also administered another therapeutic agent with at least one dose of anti-IL-2r antibody.

16. The method of claim 15, wherein the other therapeutic agent is a corticosteroid.

17. The method claim 16, wherein the corticosteroid is prednisone.

18. The method of claim 15, wherein the other therapeutic agent is selected from the group consisting of cyclosporine, cyclophosphamide, chlorambucil, cyclosporine, tacrolimus, sirolimus, levamisole, and mycophenolate mofetil.

19. A method for determining an individual dose of anti-IL-2r antibody effective in treating an idiopathic nephrotic syndrome disease comprising: providing a patient having an idiopathic nephrotic syndrome disease; administering to the patient an amount of anti-IL-2r antibody; and determining the amount of anti-IL-2r antibody receptor saturation; wherein the amount of anti-IL-2r antibody receptor saturation is indicative of the dose of anti-IL-2r antibody required by the patient.

20. A method for determining an individual dose of anti-IL-2r antibody effective in treating an idiopathic nephrotic syndrome disease comprising: providing a patient having an idiopathic nephrotic syndrome disease; administering to the patient an amount of anti-IL-2r antibody; and determining the fractional excretion of IgG; wherein the fractional excretion of

IgG is indicative of the dose of anti-IL-2r antibody required by the patient.