WO2009145831A1 - Traitement des maladies à spectre de syndrome néphrotique idiopathique à l'aide de basiliximab - Google Patents

Traitement des maladies à spectre de syndrome néphrotique idiopathique à l'aide de basiliximab Download PDF

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Publication number
WO2009145831A1
WO2009145831A1 PCT/US2009/002049 US2009002049W WO2009145831A1 WO 2009145831 A1 WO2009145831 A1 WO 2009145831A1 US 2009002049 W US2009002049 W US 2009002049W WO 2009145831 A1 WO2009145831 A1 WO 2009145831A1
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Prior art keywords
antibody
patient
nephrotic syndrome
disease
treatment
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PCT/US2009/002049
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English (en)
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Glen H. Bock
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Geisinger Clinic
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • 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.
  • Basiliximab chimeric monoclonal anti-interleukin-2 receptor antibody
  • Idiopathic nephrotic syndrome 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.
  • 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.
  • a monoclonal antibody mab
  • IL-2r IL-2 receptor
  • basiliximab receptor-activation
  • 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.
  • the initial dose given on day 1 of the dosing period may be larger than the subsequent doses given during the period.
  • all of the doses in the dosing period be the same amount.
  • 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.
  • 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.
  • 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.
  • 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
  • Figure 3 is a graph of the serum cholesterol for each treatment period for the patient of the Example.
  • Figure 4 is a graph of vascular permeability in nephrotic syndrome before and after corticosteroid treatment based on data from Rostoker et al. (4).
  • 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
  • the present invention provides methods for determining the success of a treating an INSS disease using basiliximab.
  • Basiliximab is a chimeric mouse-human monoclonal
  • IgG antibody to the Interleukin-2 receptor ⁇ -chain CD25, anti-IL-2r
  • 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
  • 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)
  • 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.
  • an anti -IL-2r mab is used to treat an
  • the anti -IL-2r mab may be administered alone or in conjunction with traditional treatments.
  • 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.
  • 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
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • methods are provided for determining a dosage of anti -IL-2r mab for treatment of INSS diseases.
  • 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.
  • 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.
  • the profile of protein losses in nephrotic and proteinuric conditions can vary considerably.
  • [IgGxxx] concentration of IgG in g/dL
  • 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.
  • INS idiopathic nephrotic syndrome
  • FSGS focal segmental glomerulosclerosis
  • INS idiopathic nephrotic syndrome
  • FSGS focal segmental glomerulosclerosis
  • CS corticosteroid
  • 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.
  • IL-2 Interleukin-2
  • 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.
  • anti-IL-2 receptor monoclonal antibodies can abrogate IL-2 induced T cell proliferation, we considered their potential benefit in INS.
  • a multi-drug resistant INS patient was treated with the chimeric anti-IL2 receptor monoclonal antibody, basiliximab (BIx).
  • 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.
  • 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
  • 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
  • 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.
  • Period 1 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.
  • 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).
  • 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
  • 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.
  • 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.
  • the degree of proteinuria gradually increased in both patients although Patient 2 remains edema-free.

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Abstract

L'invention porte sur des procédés de traitement des maladies à spectre de syndrome néphrotique idiopathique (INSS) à l'aide d'anticorps dirigés contre le récepteur de l'IL-2 (anticorps anti-IL-2r) de lymphocytes T, tels que le basiliximab. Les procédés peuvent être utilisés pour traiter le large spectre des maladies à INSS à la fois chez les enfants et les adultes.
PCT/US2009/002049 2008-04-02 2009-04-02 Traitement des maladies à spectre de syndrome néphrotique idiopathique à l'aide de basiliximab WO2009145831A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017011772A1 (fr) * 2015-07-16 2017-01-19 Abbvie, Inc. Traitement du syndrome néphrotique à résistance multimédicamenteuse (mdr-ns) chez les enfants
WO2017068421A1 (fr) 2015-10-22 2017-04-27 Juno Therapeutics Gmbh Procédés, kits et appareil de culture de cellules
WO2018094021A1 (fr) * 2016-11-16 2018-05-24 The Research Institute At Nationwide Children's Hospital Résistance aux stéroïdes dans le syndrome néphrotique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002081508A2 (fr) * 2001-04-06 2002-10-17 University Of Bristol Utilisation de molecules de liaison cd25 chez des patients resistants aux steroides
US20050112130A1 (en) * 2003-11-05 2005-05-26 Bhat Neelima M. Enhanced B cell cytotoxicity of CDIM binding antibody

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002081508A2 (fr) * 2001-04-06 2002-10-17 University Of Bristol Utilisation de molecules de liaison cd25 chez des patients resistants aux steroides
US20050112130A1 (en) * 2003-11-05 2005-05-26 Bhat Neelima M. Enhanced B cell cytotoxicity of CDIM binding antibody

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANNE-LAURE SELLIER-LECLERC ET AL: "A humanized mouse model of idiopathic nephrotic syndrome suggest a pathogenic role for immature cells", JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, vol. 18, no. 10, October 2007 (2007-10-01), pages 2732 - 2739 *
SALLY-ANNE HULTON ET AL: "Lymphocyte subpopulations, interleukin-2 and interleukin -2 receptor expression in childhood nephrotic syndrome", PEDIATRIC NEPHROLOGY, vol. 8, no. 2, April 1994 (1994-04-01), pages 135 - 139 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017011772A1 (fr) * 2015-07-16 2017-01-19 Abbvie, Inc. Traitement du syndrome néphrotique à résistance multimédicamenteuse (mdr-ns) chez les enfants
WO2017068421A1 (fr) 2015-10-22 2017-04-27 Juno Therapeutics Gmbh Procédés, kits et appareil de culture de cellules
US11466253B2 (en) 2015-10-22 2022-10-11 Juno Therapeutics Gmbh Methods for culturing cells and kits and apparatus for same
WO2018094021A1 (fr) * 2016-11-16 2018-05-24 The Research Institute At Nationwide Children's Hospital Résistance aux stéroïdes dans le syndrome néphrotique

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