Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2866—Immunoglobulins [IG], 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • 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

Definitions

• CD25 binding molecules for use in the treatment of manifestations of rejection in transplantation
• the invention is directed to the use of a CD25 binding molecule in the treatment of rejection in transplantation.
• a serious problem following transplantation is associated with the fact that transplant patients receive a long-term immunosuppression, a so-called triple therapy composed of a calcineurin inhibitor like cyclosporin A or FK-506, a steroid and a concomitant immunosup- pressant like azathioprine, mycophenolic acid, mycophenolate mofetil, a 15-deoxyspergua- line, rapamycin or 40-O-(2-hydroxy)ethyl-rapamycin (RAD001).
• IGF-2R interleukin-2 receptor
• induction treatment i.e. as prophylactic short-term immunosuppressants for single or multiple administration in the very early phase following transplantation, e.g. shortly before the transplantation and up to 3 months after transplantation.
• a period of time beyond the very early phase following transplantation is that period of time that begins some weeks, months or even years after transplantation depending on the nature of the side effects and on the patient's perception of the severity of the side effects, and may last for the rest of life of the transplant recipient.
• the reduction in calcineurin inhibi- tor dose may occur in the first weeks because of immediate side effects, or, especially in paediatric patients, much later as the patient matures and becomes aware of cosmetic changes that can effect social behaviour.
• Compounds suitable for the purposes of this invention include monoclonal antibodies specific for the a subunit of IL-2R ( ⁇ 55 kDa), CD25, i.e. IL-2R ⁇ , e.g. a humanized antibody, e.g. a humanized antibody having two pairs of light/heavy chain dimers, wherein each chain comprises complementarity determining regions (CDR's) and human-like framework regions, wherein the CDR's are from different immunoglobulin molecules than the framework regions, or a chimeric antibody, e.g.
• a chimeric antibody which comprises at least one antigen binding site comprising at least one domain which comprises in sequence, the hypervariable regions CDR1 , CDR2 and CDR3; said CDR1 having the amino acid sequence Arg-Tyr-Trp-Met-His, said CDR2 having the amino acid sequence Ala-lle-Tyr-Pro-Gly-Asn- Ser-Asp-Thr-Ser-Tyr-Asn-Gln-Lys-Phe-Glu-Gly, and said CDR3 having the amino acid sequence Asp-Tyr-Gly-Tyr-Tyr-Phe-Asp-Phe; or direct equivalents thereof.
• Humanized antibodies have been disclosed together with processes for their preparation in WO 90/07861 , the content of which is incorporated herein by reference. These antibodies have, on the basis of observed activity in e.g. a test to determine antibody-dependent cell mediated cytotoxicity, been found to be useful as immunosuppressant for the prevention of graft rejection.
• An individual antibody of WO 90/07861 is multiply administered to transplant patients during the first three months following transplantation.
• Chimeric antibodies have been disclosed together with processes for their preparation in EP 449,769, the content of which is incorporated herein by reference. These antibodies have, on the basis of observed activity in e.g. a test to determine cell proliferation, been found to be useful as immunosuppressant for the prevention of graft rejection.
• An individual antibody of EP 449,769, basiliximab, is twice administered to transplant patients on the day of transplantation and 4 days later.
• Individual antibodies suitable for use in accordance with the present invention are the humanized antibody daclizumab and the chimeric antibody basiliximab.
• a preferred compound for use in accordance with the present invention is basiliximab which is commercially available as SIMULECT ® from Novartis.
• a method of preventing or treating transplant rejection in a recipient of organ, tissue or unmodified or modified cell transplant e.g. heart, lung, combined heart-lung, trachea, liver, kidney, pancreas, Islet cell, bowel, e.g. small bowel, skin, muscles or limb, bone marrow, oesophagus, cornea or nervous tissue transplant, which method comprises long-term administering to said recipient an effective amount of a monoclonal antibody specific for IL-2R, e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab, over a period of time beyond the very early phase following transplantation.
• a monoclonal antibody specific for IL-2R e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab
• a method of preventing or treating rejection in an immunosuppression-intolerant or -non- compliant recipient of organ, tissue or unmodified or modified cell transplant e.g. heart, lung, combined heart-lung, trachea, liver, kidney, pancreas, Islet cell, bowel, e.g. small bowel, skin, muscles or limb, bone marrow, oesophagus, cornea or nervous tissue transplant, which method comprises long-term administering to said recipient an effective amount of a monoclonal antibody specific for IL-2R, e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab, over a period of time beyond the very early phase following transplantation.
• a monoclonal antibody specific for IL-2R e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab
• the organ, tissue or unmodified or modified cell transplant may be of human (allotransplan- tation) or non-human, e.g. pig, (xenotransplantation) origin.
• the present invention provides:
• a method of preventing or treating xenotransplant rejection in a recipient of an organ, tissue or unmodified or modified cell xenotransplant e.g. heart, lung, combined heart-lung, trachea, liver, kidney, pancreas, Islet cell, bowel, e.g. small bowel, skin, muscles or limb, bone marrow, oesophagus, cornea or nervous tissue transplant
• a monoclonal antibody specific for IL- 2R e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab.
• a method of preventing or treating rejection in a recipient of an organ, tissue or unmodified or modified cell xenotransplant e.g. heart, lung, combined heart-lung, trachea, liver, kidney, pancreas, Islet cell, bowel, e.g. small bowel, skin, muscles or limb, bone marrow, oesophagus, cornea or nervous tissue transplant, which method comprises administering to said recipient an effective amount of a monoclonal antibody specific for IL-2R, e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab.
• a monoclonal antibody specific for IL-2R e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab.
• a monoclonal antibody specific for IL-2R e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab, for use in any method as defined under 1 to 3 above; or
• a monoclonal antibody specific for IL-2R e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab, for use in the preparation of a pharmaceutical composition for use in any method as defined under 1 to 3 above; or
• a pharmaceutical composition for use in any method as defined under 1 to 3 above comprising a monoclonal antibody specific for IL-2R, e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab, together with one or more pharmaceutically acceptable diluents or carriers therefor.
• a monoclonal antibody specific for IL-2R e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab, together with one or more pharmaceutically acceptable diluents or carriers therefor.
• a monoclonal antibody specific for IL-2R e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab, in preventing transplant rejection as hereinabove specified, may be demonstrated in clinic where e.g. the transplanted organ, tissue or unmodified or modified cell transplant may be submitted to regular controls, e.g. to biopsy controls or ultrasound scanning. Daclizumab may be useful as rescue treatment when the first symptoms of rejection occur.
• 30 patients intolerant to cyclosporine A are randomized to one of two treatment groups; those receiving a maintenance dose of Sandimmun Neoral ® sufficient to achieve cyclosporine A trough levels above 200 ng/ml and those receiving a maintenance dose of Sandimmun Neoral ® sufficient to achieve cyclosporine A trough levels above 100 ng/ml + a monoclonal antibody specific for IL-2R, e.g. basiliximab or daclizumab.
• the patients are also on stable doses of prednisone.
• the monoclonal antibody specific for IL-2R is administered intravenously at a dose of 40 mg every month.
• markers of rejection e.g. rise in creatinine or decreased GFR (for renal transplant recipients) or rising liver transaminases (for liver transplant recipients)
• calcineurin inhibitor intolerance e.g. renal dysfunction, hirsutism, hypertension, gingival and hyperplasia
• a calcineurin inhibitor intolerant patient receives a monoclonal antibody specific for IL-2R, e.g. a humanized or chimeric monoclonal antibody specific for IL-2R, especially basiliximab or daclizumab, and a reduced dosage of a calcineurin inhibitor, e.g. cyclosporine A, side effects of the calcineurin inhibitor are reduced.
• Patients receiving the lower dose of Sandimmun Neoral ® + a monoclonal antibody specific for IL-2R compared with those receiving the higher dose of Sandimmun Neoral ® and no monoclonal antibody specific for IL-2R show a satisfactory level of immunosuppression.
• the monoclonal antibody specific for IL- 2R e.g. basiliximab or daclizumab is effective when administered at a dose of 40 mg every month.
• a monoclonal antibody specific for IL-2R e.g. basiliximab or daclizumab
• xenotransplantation may be tested clinically.
• the appropriate dosage will, of course, vary depending upon, for example, the particular molecule to be employed, the host, the mode of administration and the severity of the condition being treated and the effects obtained. Satisfactory results are generally indicated to be obtained at dosages in the range of from about 0.1 mg to about 500 mg, e.g. of from 10 mg to 150 mg, especially 40 mg or 20 mg.
• administration of a dose in the range of from 10 to 150 mg, especially 40 mg may be on a weekly or monthly basis, for example every week, every two, three, four, five, six, seven or eight weeks, regularly or irregularly, as required.
• An exemplary dosing regimen for preventing or treating rejection in an immunosuppression- intolerant or -non-compliant recipient of organ, tissue or unmodified or modified cell transplant beyond the very early phase following transplantation is long-term monthly intravenous administration of 40 mg.
• administration of a dose in the range of from 10 to 150 mg, especially 20 mg may be within a day prior to transplantation followed by a single dose in the range of from 10 to 150 mg, especially 20 mg, within a week following transplantation or by one to 10 doses in the range of from 10 to 150 mg, especially 20 mg, for up to 10 weeks following transplantation; optionally followed by administration as often as indicated on a weekly or monthly basis, for example a dose in the range of from 10 to 150 mg, especially 40 mg, may be administered every week, every two, three, four, five, six, seven or eight weeks, regularly or irregularly, as required.
• An exemplary dosing regimen for preventing rejection in a xenograft transplantation recipient is intravenous administration of 20 mg two hours prior to transplantation and 20 mg 4 days later; or 20 mg two hours prior to transplantation, 20 mg 4 days later, followed by monthly intravenous administration of 40 mg.
• Another exemplary dosing regimen for preventing rejection in a xenograft transplantation recipient is intravenous administration of 5 times 1 mg/kg body weight over 8 weeks; or intravenous administration of 1 mg/kg body weight every 10 days; or 5 times 1 mg/kg body weight over 8 weeks, followed by monthly intravenous administration of 2 mg/kg body weight.
• compositions of the invention may be manufactured in a conventional manner as described, e.g. in EP 449769 or WO 90/07861.
• the composition may e.g. be prepared for storage as lyophilized powder in a vial.
• the solution for parenteral administration may conveniently be prepared shortly before administration.
• the monoclonal antibodies specific for IL-2R may be administered together with other drugs in immunomodulating regimens or other anti-inflammatory agents.
• the monoclonal antibodies specific for IL-2R may be used in combination with cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g.
• cyclosporin A cyclosporin G, FK- 506, RAD001 , rapamycin etc.
• corticosteroids cyclophosphamide
• azathioprine metho- trexate; brequinar
• leflunomide mizoribine
• mycophenolic acid mycophenolate mofetil
• Murine monoclonal antibodies suitable for use together with the monoclonal antibody are described in EP 449,769.
• a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a monoclonal antibody specific for IL-2R and a second drug substance, said second drug substance being an immunosuppressant or immunomodulatory drug, e.g. as indicated above.
• kits include for example a multi-barrelled syringe or a twin pack containing separate unit dose forms.
• basiliximab is safe, approved by the Federal Drug Administration (FDA) of the United States and is commercially available.

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• Health & Medical Sciences (AREA)
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• Proteomics, Peptides & Aminoacids (AREA)
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• Engineering & Computer Science (AREA)
• Biochemistry (AREA)
• Transplantation (AREA)
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• Animal Behavior & Ethology (AREA)
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• Pharmacology & Pharmacy (AREA)
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• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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• 1998
  • 1998-11-23 GB GBGB9825632.4A patent/GB9825632D0/en not_active Ceased
• 1999
  • 1999-11-22 JP JP2000583562A patent/JP2002530354A/ja active Pending
  • 1999-11-22 WO PCT/EP1999/008988 patent/WO2000030679A1/en not_active Ceased
  • 1999-11-22 EP EP99972545A patent/EP1131098A1/en not_active Withdrawn
  • 1999-11-22 AU AU13846/00A patent/AU1384600A/en not_active Abandoned
• 2001
  • 2001-05-22 US US09/862,212 patent/US20010041179A1/en not_active Abandoned
• 2008
  • 2008-07-28 US US12/180,660 patent/US20080286281A1/en not_active Abandoned

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