Combinations and methods for subcutaneous administration of immune globulin and hyaluronidase

Abstract

Provided are combinations, compositions and kits containing a immune globulin (IG) composition and a soluble hyaluronidase composition formulated for subcutaneous administration. Such products can be used in methods of treating IG-treatable diseases or conditions. Also provided are methods for subcutaneous administration of immune globulin whereby the dosing regimen is substantially the same as for intravenous administration of the same dosage for treatment of the same IG-treatable disease or condition.

The invention claimed is: 
     
       1. A method for treating an IG-treatable disease or condition in a subject, comprising subcutaneously administering to the subject no more than once monthly a soluble hyaluronidase and an immune globulin (IG) composition for treating the disease or condition, wherein:
 the IG is from human plasma; 
 the IG and hyaluronidase are administered separately; 
 the hyaluronidase is administered prior to administration of the IG; 
 the IG composition has a protein concentration that is 5 to 25% w/v IG; 
 the IG is administered at a dosage of 100 mg per kg body weight (100 mg/kg BW) to 2 g/kg BW; and 
 the hyaluronidase is administered at a ratio of Units hyaluronidase per gram of IG that is in the range of about 10 to 500 Units hyaluronidase per gram of the IG, whereby the dose of IG administered is a full monthly dose. 
 
     
     
       2. The method of  claim 1 , wherein the soluble hyaluronidase is an ovine PH20, bovine PH20 or a soluble human PH20, wherein the soluble human PH20 is a C-terminally truncated PH20 that lacks all or a portion of the glycosylphosphatidylinositol (GPI) anchor attachment sequence. 
     
     
       3. The method of  claim 1 , wherein the soluble hyaluronidase is selected from among a polypeptide having a sequence of amino acids set forth in any of SEQ ID NOS:4-9. 
     
     
       4. The method of  claim 1 , wherein:
 the IG is administered in a volume of 50 mL to 700 mL; and 
 the hyaluronidase is administered in a volume of less than 50 mL. 
 
     
     
       5. The method of  claim 1 , wherein the IG composition is administered as a liquid solution in a volume of 50 mL to 700 mL. 
     
     
       6. The method of  claim 1 , wherein the pH of the IG preparation composition is at or about 4.8 to 5.0. 
     
     
       7. The method of  claim 1 , wherein the pH of the IG preparation composition is at or about 4.6 to 5.1. 
     
     
       8. The method of  claim 1 , wherein the pH of the IG preparation composition is at or about 4.2 to 5.4. 
     
     
       9. The method of  claim 1 , wherein 20-30 grams (g) IG is administered. 
     
     
       10. The method of  claim 1 , wherein about or 5 grams (g), 10 g, 15 g, 20 g, 21 g, 22 g, 23 g, 24 g, 25 g, 26 g, 27 g, 28 g, 29 g, 30 g, 31 g, 32 g, 33 g, 34 g, 35 g, 36 g, 37 g, 38 g, 39 g or 40 g of IG is administered. 
     
     
       11. The method of  claim 1 , wherein at least 5 grams (g) of IG is administered. 
     
     
       12. The method of  claim 1 , wherein the IG is administered at a dosage of at least 200 mg/kg BW, 300 mg/kg BW, 400 mg/kg BW, 500 mg/kg BW or 600 mg/kg BW. 
     
     
       13. The method of  claim 1 , wherein the IG is administered at 600 mg/kg body weight (BW) and the soluble hyaluronidase is administered at a ratio of 50 units hyaluronidase/gram of IG. 
     
     
       14. The method of  claim 1 , wherein the hyaluronidase is administered in a volume of less than 50 mL. 
     
     
       15. The method of  claim 1 , wherein the hyaluronidase is administered in a volume of 5-30 mL. 
     
     
       16. The method of  claim 1 , wherein bioavailability of the subcutaneously administered IG is at least about 90% of the bioavailability of the same dosage administered via IV administration. 
     
     
       17. The method of  claim 1 , wherein the soluble hyaluronidase is a PH20,or a truncated form thereof. 
     
     
       18. The method of  claim 17 , wherein the PH20 is selected from an ovine, bovine or truncated human PH20. 
     
     
       19. The method of  claim 18 , wherein the PH20 is a truncated human PH20 selected from among a polypeptide having a sequence of amino acids set forth in any of SEQ ID NOS:4-9, or a variant thereof that has at least 95% sequence identity with any of SEQ ID NOS:4-9, is soluble and exhibits hyaluronidase activity. 
     
     
       20. The method of  claim 18 , wherein the truncated human PH20 is selected from among a polypeptide having a sequence of amino acids set forth in any of SEQ ID NOS:4-9. 
     
     
       21. The method of  claim 1 , wherein the soluble hyaluronidase is designated rHuPH20. 
     
     
       22. The method of  claim 1 , wherein the IG is purified from human plasma. 
     
     
       23. The method of claim  22  1, wherein the IG purified from human plasma is purified by alcohol fractionation. 
     
     
       24. The method of  claim 23 , wherein the IG is further purified by any one or more of a chemical modification, so incubation at pH 4.0 with or without pepsin, polyethylene glycol (PEG) precipitation, ion-exchange chromatography, enzymatic cleavage, solvent detergent treatment, diafiltration or ultrafiltration. 
     
     
       25. The method of  claim 1 , wherein the IG composition contains IgG, IgA and IgM. 
     
     
       26. The method of  claim 25 , wherein the IG composition contains greater than 95% IgG. 
     
     
       27. The method of  claim 26 , wherein the IgG is monomeric. 
     
     
       28. The method of  claim 1 , wherein the IG composition further contains protein-stabilizing excipients. 
     
     
       29. The method of  claim 28 , wherein the protein-stabilizing excipient is selected from among one or more of glycine, maltose, a polyol, human serum albumin, mannitol, and non-ionic detergent. 
     
     
       30. The method of  claim 1 , wherein the pH of the IG preparation composition is at or about 4.2 to 5.4, 4.6 to 5.1 or 4.8 to 5.0. 
     
     
       31. The method of  claim 30 , wherein the IG composition has a protein concentration that is or is about 5 to 15% w/v, 6 to 15% w/v, or 8 to 12% w/v of IG composition. 
     
     
       32. The method of  claim 30 , wherein the IG has a protein concentration that is or is about 5 to 15% w/v of IG composition. 
     
     
       33. The method of  claim 31 , wherein the protein concentration is 10% w/v. 
     
     
       34. The method of  claim 1 , where the IG composition is administered as a liquid solution and the volume of liquid is or is about to 100 ml, 150 ml, 200 ml, 300 ml, 400 ml, 500 ml, 600 ml or 700 ml. 
     
     
       35. The method of  claim 1 , wherein the IG composition is infused at a rate of 10 ml/hr to 300 ml/hr. 
     
     
       36. The method of  claim 35 , wherein the rate is selected is from among at or about 10 ml/hr, 20 ml/hr, 30 ml/hr, 40 ml/hr, 50 ml/hr, 60 ml/hr, 70 ml/hr, 80 ml/hr, 90 ml/hr, 100 ml/hr, 150 ml/hr, 200 ml/hr, 250 ml/hr and 300 ml/hr. 
     
     
       37. The method of  claim 35 , wherein the rate is controlled by a pump. 
     
     
       38. The method of  claim 35 , wherein the rate is controlled by gravity. 
     
     
       39. The method of  claim 1 , wherein the hyaluronidase is administered 0.5 minutes, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 20 minutes or 30 minutes prior to administration of IG. 
     
     
       40. The method of  claim 1 , wherein the hyaluronidase is administered at a ratio (units hyaluronidase/grams of IG) at or about 10 U/gram (g), 20 U/g, 30 U/g, 35 U/g, 40 U/g, 50 U/g, 60 U/g, 70 U/g, 80 U/g, 90 U/g, 100 U/g, 150 U/g, or 300 U/g. 
     
     
       41. The method of  claim 40 , wherein the hyaluronidase is administered at a ratio of or about 50 U/gram IG. 
     
     
       42. The method of  claim 1 , wherein the hyaluronidase that is administered is at or about 10 Units to 500,000 Units, 100 Units to 100,000 Units, 500 Units to 50,000 Units, 1000 Units to 10,000 Units, 5000 Units to 7500 Units, 5000 Units to 50,000 Units, or 1,000 Units to 10,000 Units. 
     
     
       43. The method of  claim 1 , wherein the IG-treatable disease or condition is selected from among immunodeficiency; acquired hypogammaglobulinemia secondary to hematological malignancies; Kawasaki's disease; chronic inflammatory demyelinating polyneuropathy (CIDP); Guillain-Barre Syndrome; Idiopathic thrombocytopenic purpura; inflammatory myopathies; Lambert-Eaton myasthenic syndrome; multifocal motor neuropathy; Myasthenia Gravis; Moersch-Woltmann syndrome; secondary hypogammaglobulinaemia specific antibody deficiency; Acute disseminated encephalomyelitis; ANCA-positive systemic necrotizing vasculitis; Autoimmune haemolytic anaemia; Bullous pemphigoid; Cicatricial pemphigoid; Evans syndrome; Foeto-maternal/neonatal alloimmune thrombocytopenia (FMAIT/NAIT); Haemophagocytic syndrome; high-risk allogeneic haemopoietic stem cell transplantation; IgM paraproteinaemic neuropathy; kidney transplantation; multiple sclerosis; Opsoclonus myoclonus ataxia; Pemphigus foliaceus; Pemphigus vulgaris; Post-transfusion purpura; Toxic epidermal necrolysis/Steven Johnson syndrome (TEN/SJS); Toxic shock syndrome; Alzheimer's Disease; Systemic lupus erythematosus; multiple myeloma; sepsis; B cell tumors; trauma; and a bacterial, viral or fungal infection. 
     
     
       44. The method of  claim 43 , wherein the IG-treatable disease or condition is an immunodeficiency and the immunodeficiency is selected from among common variable immunodeficiency (CVID), congenital agammaglobulinemia, Wiskott-Aldrich syndrome, severe combined immunodeficiency (SCID), primary hypogammaglobulinemia, primary immunodeficiency diseases with antibody deficiency, X-linked agammaglobulinemia (XLA), hypogammaglobulinemia of infancy, and paraneoplastic cerebellar degeneration with no antibodies. 
     
     
       45. The method of  claim 43 , wherein the IG-treatable disease or condition is acquired hypogammaglobulinemia secondary to hematological malignancies and the hematological malignancy is selected from among chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). 
     
     
       46. The method of  claim 43 , wherein the IG-treatable disease or condition is an inflammatory myopathy and the inflammatory myopathy is selected from among polymyositis, dermatomyositis and inclusion body myositis. 
     
     
       47. The method of  claim 43 , wherein the IG-treatable disease or condition is a bacteria, viral or fungal condition and the bacterial viral or fungal condition is selected from among Haemophilus influenzae type B, Pseudomonas aeruginosa types A and B, Staphylococcus aureus, Group B Streptococcus, Streptococcus pneumoniae types 1, 3, 4, 6, 7, 8, 9, 12, 14, 18, 19, and 23, Adenovirus types 2 and 5, Cytomegalovirus, Epstein Barr virus VCA, Hepatitis A virus, Hepatitis B virus, Herpes simplex virus-1, Herpes simplex virus-2, Influenza A, Measles, Parainfluenza types 1, 2 and 3, Polio, Varicella zoster virus, Aspergillus and Candida albicans. 
     
     
       48. The method of claim 1, wherein the IG composition has a protein concentration of from about 8 to about 12% w/v of IG.  
     
     
       49. The method of claim 1, wherein the IG composition has a protein concentration of from about 15 to about 25% w/v of IG.  
     
     
       50. The method of claim 1, wherein the IG composition has a protein concentration of from about 20 to about 25% w/v of IG.  
     
     
       51. The method of claim 1, wherein the soluble hyaluronidase comprises an amino acid sequence that is at least about 95% identical to SEQ ID NO:9.  
     
     
       52. The method of claim 1, wherein the soluble hyaluronidase comprises the amino acid sequence of SEQ ID NO:9.  
     
     
       53. The method of claim 1, wherein the IG is administered at from about 300 mg/kg BW to about 600 mg/kg BW.  
     
     
       54. The method of claim 1, wherein the IG-treatable disease or condition is a primary immunodeficiency.  
     
     
       55. The method of claim 1, wherein the IG-treatable disease or condition is chronic inflammatory demyelinating polyneuropathy.  
     
     
       56. A method for treating an immune globulin (IG)-treatable disease or condition in a subject, comprising:
 subcutaneously administering a hyaluronidase composition comprising a soluble hyaluronidase at one or more sites on the subject;   after administering the hyaluronidase composition, subcutaneously administering an IG composition comprising IG for treating the disease or condition at the one or more sites on the subject, wherein:
 the IG is from human plasma, 
 the IG composition has a protein concentration of from about 5 to about 25% w/v IG, 
 the subject is administered an IG dosage of from about 100 mg per kg body weight (mg/kg BW) to about 2 g/kg BW, and 
 the subject is administered a soluble hyaluronidase dosage at a ratio of from about 10 to about 500 Units hyaluronidase per gram of the administered IG; 
   wherein the hyaluronidase composition and the IG composition are subcutaneously administered to the subject no more frequently than once every three weeks.    
     
     
       57. The method of claim 56, wherein the IG-treatable disease or condition is selected from among immunodeficiency; acquired hypogammaglobulinemia secondary to hematological malignancies; Kawasaki's disease; chronic inflammatory demyelinating polyneuropathy (CIDP); Guillain-Barre Syndrome; Idiopathic thrombocytopenic purpura; inflammatory myopathies; Lambert-Eaton myasthenic syndrome; multifocal motor neuropathy; Myasthenia Gravis; Moersch-Woltmann syndrome; secondary hypogammaglobulinaemia specific antibody deficiency; Acute disseminated encephalomyelitis; ANCA-positive systemic necrotizing vasculitis; Autoimmune haemolytic anaemia; Bullous pemphigoid; Cicatricial pemphigoid; Evans syndrome; Foeto-maternal/neonatal alloimmune thrombocytopenia (FMAIT/NAIT); Haemophagocytic syndrome; high-risk allogeneic haemopoietic stem cell transplantation; IgM paraproteinaemic neuropathy; kidney transplantation; multiple sclerosis; Opsoclonus myoclonus ataxia; Pemphigus foliaceus; Pemphigus vulgaris; Post-transfusion purpura; Toxic epidermal necrolysis/Steven Johnson syndrome (TEN/SJS); Toxic shock syndrome; Alzheimer's Disease; Systemic lupus erythematosus; multiple myeloma; sepsis; B cell tumors; trauma; and a bacterial, viral or fungal infection.  
     
     
       58. The method of claim 56, wherein the IG-treatable disease or condition is a primary immunodeficiency.  
     
     
       59. The method of claim 56, wherein the IG-treatable disease or condition is chronic inflammatory demyelinating polyneuropathy.  
     
     
       60. The method of claim 56, wherein the hyaluronidase composition administered to the subject has a volume of less than about 50 mL.  
     
     
       61. The method of claim 56, wherein the soluble hyaluronidase is a soluble human PH2O that is C-terminally truncated and lacks all or a portion of the glycosylphosphatidylinositol (GPI) anchor attachment sequence.  
     
     
       62. The method of claim 56, wherein the soluble hyaluronidase has an amino acid sequence that is at least about 95% identical to SEQ ID NO:9.  
     
     
       63. The method of claim 56, wherein the soluble hyaluronidase has an amino acid sequence of SEQ ID NO:9.  
     
     
       64. The method of claim 56, wherein the subject is administered a soluble hyaluronidase dosage at a ratio of from about 50 to about 100 Units hyaluronidase per gram of the administered IG.  
     
     
       65. The method of claim 56, wherein the pH of the IG composition is about 4.6 to about 5.1.  
     
     
       66. The method of claim 56, wherein the protein content of the IG composition comprises at least about 95% IgG.  
     
     
       67. The method of claim 56, wherein the IG composition further comprises an amino acid.  
     
     
       68. The method of claim 56, wherein the IG composition has a protein concentration of from about 5% to about 15%.  
     
     
       69. The method of claim 56, wherein the IG composition has a protein concentration of from about 15 to about 25% w/v of IG.  
     
     
       70. The method of claim 56, wherein the IG composition has a protein concentration of about 10% w/v of IG.  
     
     
       71. The method of claim 56, wherein the IG composition has a protein concentration of from about 20 to about 25% w/v of IG.  
     
     
       72. The method of claim 56, wherein the IG composition is administered to the subject at an infusion rate of from about 10 mL/hr to about 300 mL/hr.  
     
     
       73. The method of claim 56, wherein the IG composition is administered to the subject at an infusion rate of from about 120 mL/hr to about 300 mL/hr.  
     
     
       74. The method of claim 56, wherein the IG composition is administered to the subject at an infusion rate of at least about 200 mL/hr.  
     
     
       75. The method of claim 56, wherein the IG composition is started within about 20 minutes of completion of administration of the hyaluronidase composition.  
     
     
       76. The method of claim 56, wherein the IG composition is started within about 10 minutes of completion of administration of the hyaluronidase composition.  
     
     
       77. The method of claim 56, wherein the subject is administered an IG dosage of from about 300 mg/kg BW to about 600 mg/kg BW.  
     
     
       78. The method of claim 56, wherein the bioavailability of the subcutaneously administered IG is at least about 80% of the bioavailability of the same dosage of IG administered via intravenous (IV) administration.  
     
     
       79. The method of claim 56, wherein the soluble hyaluronidase is selected from among a polypeptide having a sequence of amino acids set forth in any of SEQ ID NOS:4-9.