High concentration anti-c5 antibody formulations

Abstract

The present disclosure relates to stable aqueous solutions comprising a high concentration of an anti-C5 antibody (e.g., ravulizumab) and methods for preparing the solutions. The disclosure also provides methods for treating or preventing complement-associated disorders, such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), using the solutions. Also featured were therapeutic kits containing one or more of the solutions and a means for administering the solutions to a patient in need such a treatment.

1 - 31 . (canceled) 
     
     
         32 . A method of treating a human patient with a complement-associated condition, comprising administering to the patient a stable aqueous solution in an amount effective to treat the complement-associated condition, wherein the stable aqueous solution comprises:
 (a) an anti-C5 antibody at a concentration of about 100 mg/mL, wherein the anti-C5 antibody comprises a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:19, a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:18, a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:3, a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:4, a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:5, and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:6;   (b) about 50 mM Phosphate Buffer;   (c) about 5% sucrose; and   (d) about 25 mM Arginine.   
     
     
         33 . A method of treating a human patient with a complement-associated condition, comprising administering to the patient a stable aqueous solution in an amount effective to treat the complement-associated condition, wherein the stable aqueous solution comprises:
 (a) an anti-C5 antibody, wherein the anti-C5 antibody comprises a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:19, a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:18, a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:3, a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:4, a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:5, and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:6;   (b) about 50 mM Phosphate Buffer;   (c) about 5% sucrose;   (d) about 0.05% Polysorbate 80; and   (e) about 25 mM Arginine.   
     
     
         34 . The method of  claim 32  or  33 , wherein the solution further comprises a surfactant. 
     
     
         35 . The method of  34 , wherein the surfactant is about 0.04%-0.07% Polysorbate 80. 
     
     
         36 . The method of  claim 34 , wherein the surfactant is about 0.05% Polysorbate 80. 
     
     
         37 . The method of  claim 33 , wherein the anti-C5 antibody is at a concentration of about 100 mg/mL. 
     
     
         38 . The method of  claim 32  or  33 , wherein the anti-C5 antibody further comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering. 
     
     
         39 . The method of  claim 32  or  33 , wherein the anti-C5 antibody comprises a heavy chain variable region depicted in SEQ ID NO:12 and a light chain variable region depicted in SEQ ID NO:8. 
     
     
         40 . The method of  claim 32  or  33 , wherein the anti-C5 antibody comprises a heavy chain constant region depicted in SEQ ID NO:13. 
     
     
         41 . The method of  claim 32  or  33 , wherein the anti-C5 antibody comprises a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 11. 
     
     
         42 . The method of  claim 32  or  33 , wherein the anti-C5 antibody is ALXN1210 (ravulizumab). 
     
     
         43 . The method of  claim 32  or  33 , wherein the pH of the solution is between 7.1 and 7.8. 
     
     
         44 . The method of  claim 32  or  33 , wherein the pH of the solution is between 7.2 and 7.6. 
     
     
         45 . The method of  claim 44 , wherein the pH of the solution is 7.4. 
     
     
         46 . The method of  claim 32  or  33 , wherein the solution is sterile. 
     
     
         47 . The method of  claim 32  or  33 , wherein:
 (a) the anti-C5 antibody remains at least 97% monomeric during storage at 2° C. to 8° C. for at least six months as determined by SEC-HPLC; 
 (b) less than 3% of the anti-C5 antibody in the solution is aggregated as determined by SEC-HPLC; and/or 
 (c) during storage at 2° C. to 8° C. for at least six months, the anti-C5 antibody retains at least 90% of its C5-binding activity, as compared to the anti-C5 antibody prior to storage. 
 
     
     
         48 . The method of  claim 32  or  33 , wherein the solution is administered subcutaneously or intravenously to the patient. 
     
     
         49 . The method of  claim 32  or  33 , wherein the complement-associated condition is selected from the group consisting of rheumatoid arthritis, antiphospholipid antibody syndrome, lupus nephritis, ischemia-reperfusion injury, atypical hemolytic uremic syndrome (aHUS), typical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria (PNH), dense deposit disease, neuromyelitis optica, multifocal motor neuropathy, multiple sclerosis, macular degeneration, HELLP syndrome, spontaneous fetal loss, thrombotic thrombocytopenic purpura, Pauci-immune vasculitis, epidermolysis bullosa, recurrent fetal loss, traumatic brain injury, myocarditis, a cerebrovascular disorder, a peripheral vascular disorder, a renovascular disorder, a mesenteric/enteric vascular disorder, vasculitis, Henoch-Schönlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis, immune complex vasculitis, Takayasu's disease, dilated cardiomyopathy, diabetic angiopathy, Kawasaki's disease, venous gas embolus, restenosis following stent placement, rotational atherectomy, percutaneous transluminal coronary angioplasty, myasthenia gravis, cold agglutinin disease, dermatomyositis, paroxysmal cold hemoglobinuria, antiphospholipid syndrome, Graves' disease, atherosclerosis, Alzheimer's disease, systemic inflammatory response sepsis, septic shock, spinal cord injury, glomerulonephritis, transplant rejection, Hashimoto's thyroiditis, type I diabetes, psoriasis, pemphigus, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, Goodpasture's syndrome, Degos disease, and catastrophic antiphospholipid syndrome. 
     
     
         50 . The method of  claim 49 , wherein the complement-associated condition is aHUS. 
     
     
         51 . The method of  claim 49 , wherein the complement-associated condition is PNH.